1,5-Diphenylpyrazoles

ABSTRACT

Novel 1,5 diphenylpyrazole derivatives of the formula (I), in which R 1 -R 6  have the meanings indicated in Claim  1 , are HSP90 inhibitors and can be used for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and/or modulation of HSP90 plays a role.

BACKGROUND OF THE INVENTION

The invention was based on the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

The present invention relates to compounds in which the inhibition,regulation and/or modulation of HSP90 plays a role, furthermore topharmaceutical compositions which comprise these compounds, and to theuse of the compounds for the treatment of diseases in which HSP90 playsa role.

The correct folding and conformation of proteins in cells is ensured bymolecular chaperones and is critical for the regulation of theequilibrium between protein synthesis and degradation. Chaperones areimportant for the regulation of many central functions of cells, suchas, for example, cell proliferation and apoptosis (Jolly and Morimoto,2000; Smith et al., 1998; Smith, 2001).

Heat Shock Proteins (HSPs)

The cells of a tissue react to external stress, such as, for example,heat, hypoxia, oxidative stress, or toxic substances, such as heavymetals or alcohols, with activation of a number of chaperones which areknown under the term “heat shock proteins” (HSPs).

The activation of HSPs protects the cell against damage initiated bysuch stress factors, accelerates the restoration of the physiologicalstate and results in a stress-tolerant state of the cell.

Besides this originally discovered protective mechanism promoted by HSPsagainst external stress, further important chaperone functions have alsobeen described in the course of time for individual HSPs under normalstress-free conditions. Thus, various HSPs regulate, for example,correct folding, intracellular localisation and function or regulateddegradation of a number of biologically important proteins of cells.

HSPs form a gene family with individual gene products whose cellularexpression, function and localisation differs in different cells. Thenaming and classification within the family is carried out on the basisof their molecular weight, for example HSP27, HSP70, and HSP90.

Some human diseases are based on incorrect protein folding (see review,for example, Tytell et al., 2001; Smith et al., 1998). The developmentof therapies which engages in the mechanism of the chaperone-dependentprotein folding could therefore be useful in such cases. For example,incorrectly folded proteins result in aggregation of protein withneurodegenerative progression in the case of Alzheimer's disease, priondiseases or Huntington's syndrome. Incorrect protein folding may alsoresult in loss of wild-type function, which can have the consequence ofincorrectly regulated molecular and physiological function.

HSPs are also ascribed great importance in tumour diseases. There are,for example, indications that the expression of certain HSPs correlateswith the stage of progression of tumours (Martin et al., 2000; Conroy etal., 1996; Kawanishi et al., 1999; Jameel et al., 1992; Hoang et al.,2000; Lebeau et al., 1991).

The fact that HSP90 plays a role in a number of central oncogenicsignalling pathways in the cell and certain natural products havingcancer-inhibiting activity target HSP90 has led to the concept thatinhibition of the function of HSP90 would be sensible in the treatmentof tumour diseases. An HSP90 inhibitor,17-allylamino-17-demethoxygeldanamycin (17AAG), a derivative ofgeldanamycin, is currently undergoing clinical trials.

HSP90

HSP90 represents approximately 1-2% of the total cellular protein mass.It is usually in the form of a dimer in the cell and is associated witha multiplicity of proteins, so-called co-chaperones (see, for example,Pratt, 1997). HSP90 is essential for the vitality of cells (Young etal., 2001) and plays a key role in the response to cellular stress byinteraction with many proteins whose native folding has been modified byexternal stress, such as, for example, heat shock, in order to restorethe original folding or to prevent aggregation of the proteins (Smith etal., 1998).

There are also indications that HSP90 is of importance as buffer againstthe effects of mutations, presumably through correction of incorrectprotein folding caused by the mutation (Rutherford and Lindquist, 1998).In addition, HSP90 also has a regulatory importance. Under physiologicalconditions, HSP90, together with its homologue in the endoplasmaticreticulum, GRP94, plays a role in the cell balance for ensuring thestability of the conformation and maturing of various client keyproteins. These can be divided into three groups: receptors for steroidhormones, Ser/Thr or tyrosine kinases (for example ERBB2, RAF-1, CDK4and LCK) and a collection of various proteins, such as, for example,mutated p53 or the catalytic subunit of telomerase hTERT. Each of theseproteins takes on a key role in the regulation of physiological andbiochemical processes of cells. The preserved HSP90 family in humansconsists of four genes, cytosolic HSP90α, the inducible HSP90β isoform(Hickey et al., 1989), GRP94 in the endoplasmatic reticulum (Argon etal., 1999) and HSP75/TRAP1 in the mitochondrial matrix (Felts et al.,2000). It is assumed that all members of the family have a similar modeof action, but, depending on their localisation in the cell, bind todifferent client proteins. For example, ERBB2 is a specific clientprotein of GRP94 (Argon et al., 1999), while the type 1 receptor oftumour necrosis factor (TNFR1) or the retinoblastoma protein (Rb) havebeen found to be clients of TRAP1 (Song et al., 1995; Chen et al.,1996).

HSP90 is involved in a number of complex interactions with a largenumber of client proteins and regulatory proteins (Smith, 2001).Although precise molecular details have not yet been clarified,biochemical experiments and investigations with the aid of X-raycrystallography in recent years have increasingly been able to decipherdetails of the chaperone function of HSP90 (Prodromou et al., 1997;Stebbins et al., 1997). Accordingly, HSP90 is an ATP-dependent molecularchaperone (Prodromou et al, 1997), with dimerisation being important forATP hydrolysis. The binding of ATP results in the formation of atoroidal dimer structure, in which the two N-terminal domains come intoclose contact with one another and act as a switch in the conformation(Prodromou and Pearl, 2000).

Known HSP90 Inhibitors

The first class of HSP90 inhibitors to be discovered were benzoquinoneansamycins with the compounds herbimycin A and geldanamycin. Originally,the reversion of the malignant phenotype in fibroblasts which had beeninduced by transformation with the v-Src oncogene was detected with them(Uehara et al., 1985).

Later, a strong antitumoural activity was demonstrated in vitro (Schulteet al., 1998) and in vivo in animal models (Supko et al., 1995).

Immune precipitation and investigations on affinity matrices then showedthat the principal mechanism of action of geldanamycin involves bindingto HSP90 (Whitesell et al., 1994; Schulte and Neckers, 1998). Inaddition, X-ray crystallographic studies have shown that geldanamycincompetes for the ATP binding site and inhibits the intrinsic ATPaseactivity of HSP90 (Prodromou et al., 1997; Panaretou et al., 1998). Thisprevents the formation of the multimeric HSP90 complex, with itsproperty of functioning as chaperone for client proteins. As aconsequence, client proteins are degraded via the ubiquitin-proteasomepathway.

The geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin(17AAG) showed an unchanged property in the inhibition of HSP90, thedegradation of client proteins and antitumoural activity in cellcultures and in xenograft tumour models (Schulte et al, 1998; Kelland etal, 1999), but had significantly lower liver cytotoxicity thangeldanamycin (Page et all 1997). 17AAG is currently undergoing phaseI/II clinical trials.

Radicicol, a macrocyclic antibiotic, likewise exhibited revision of thev-Src and v-Ha-Ras-induced malignant phenotype of fibroblasts (Kwon etall 1992; Zhao et al, 1995). Radicicol degrades a large number of signalproteins as a consequence of HSP90 inhibition (Schulte et al., 1998).X-ray crystallographic studies have shown that radicicol likewise bindsto the N-terminal domain of HSP90 and inhibits the intrinsic ATPaseactivity (Roe et al., 1998).

Antibiotics of the coumarine type, as is known, bind to the ATP bindingsite of the HSP90 homolog DNA gyrase in bacteria. The coumarine,Novobiocin, binds to the carboxy-terminal end of HSP90, i.e. to adifferent site in HSP90 than the benzoquinone-ansamycins and radicicol,which bind to the N-terminal end of HSP90 (Marcu et al., 2000b).

The inhibition of HSP90 by novobiocin results in degradation of a largenumber of HSP90-dependent signal proteins (Marcu et al., 2000a).

The degradation of signal proteins, for example ERBB2, was demonstratedusing PU3, an HSP90 inhibitor derived from purines. PU3 causes cellcycle arrest and differentiation in breast cancer cell lines (Chiosis etal., 2001).

HSP90 as Therapeutic Target

Due to the participation of HSP90 in the regulation of a large number ofsignalling pathways which have crucial importance in the phenotype of atumour, and the discovery that certain natural products exert theirbiological effect through inhibition of the activity of HSP90, HSP90 iscurrently being tested as a novel target for the development of a tumourtherapeutic agent (Neckers et al., 1999).

The principal mechanism of action of geldanamycin, 17AAG, and radicicolincludes the inhibition of the binding of ATP to the ATP binding site atthe N-terminal end of the protein and the resultant inhibition of theintrinsic ATPase activity of HSP90 (see, for example, Prodromou et al.,1997; Stebbins et al., 1997; Panaretou et al., 1998). Inhibition of theATPase activity of HSP90 prevents the recruitment of co-chaperones andfavours the formation of an HSP90 heterocomplex, which causes clientproteins to undergo degradation via the ubiquitin-proteasome pathway(see, for example, Neckers et al., 1999; Kelland et al., 1999). Thetreatment of tumour cells with HSP90 inhibitors results in selectivedegradation of important proteins having fundamental importance forprocesses such as cell proliferation, regulation of the cell cycle andapoptosis. These processes are frequently deregulated in tumours (see,for example, Hostein et al., 2001). An attractive rationale for thedevelopment of an inhibitor of HSP90 is that a strong tumour-therapeuticaction can be achieved by simultaneous degradation of a plurality ofproteins which are associated with the transformed phenotype.

In detail, the present invention relates to compounds which inhibit,regulate and/or modulate HSP90, to compositions which comprise thesecompounds, and to methods for the use thereof for the treatment ofHSP90-induced diseases, such as tumour diseases, viral diseases, suchas, for example, hepatitis B (Waxman, 2002); immune suppression intransplants (Bijlmakers, 2000 and Yorgin, 2000); inflammation-induceddiseases (Bucci, 2000), such as rheumatoid arthritis, asthma, multiplesclerosis, type 1 diabetes, lupus erythematosus, psoriasis andinflammatory bowel disease; cystic fibrosis (Fuller, 2000); diseasesassociated with angiogenesis (Hur, 2002 and Kurebayashi, 2001), such as,for example, diabetic retinopathy, haemangiomas, endometriosis andtumour angiogenesis; infectious diseases; autoimmune diseases;ischaemia; promotion of nerve regeneration (Rosen et al., WO 02/09696;Degranco et al., WO 99/51223; Gold, U.S. Pat. No. 6,210,974 B1);fibrogenetic diseases, such as, for example, dermatosclerosis,polymyositis, systemic lupus, cirrhosis of the liver, keloid formation,interstitial nephritis and pulmonary fibrosis (Strehlow, WO 02/02123).

The invention also relates to the use of the compounds according to theinvention for the protection of normal cells against toxicity caused bychemotherapy, and to the use in diseases where incorrect protein foldingor aggregation is a principal causal factor, such as, for example,scrapie, Creutzfeldt-Jakob disease, Huntington's or Alzheimer's(Sittler, Hum. Mol. Genet., 10, 1307, 2001; Tratzelt et al., Proc. Nat.Acad. Sci., 92, 2944, 1995; Winklhofer et al., J. Biol. Chem., 276,45160, 2001). WO 01/72779 describes purine compounds and the use thereoffor the treatment of GRP94 (homologue or paralogue of HSP90)-induceddiseases, such as tumour diseases, where the cancerous tissue includes asarcoma or carcinoma selected from the group consisting of fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumour,leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, syringocarcinoma, sebaceous cellcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinomas, bone marrow carcinoma, bronchogenic carcinoma,renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonic carcinoma, Wilm's tumour, cervical cancer,testicular tumour, lung carcinoma, small-cell lung carcinoma, bladdercarcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, haemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma, leukaemia, lymphoma, multiple myeloma, Waldenström'smacroglobulinaemia and heavy-chain disease.

WO 01/72779 furthermore discloses the use of the compounds mentionedtherein for the treatment of viral diseases, where the viral pathogen isselected from the group consisting of hepatitis type A, hepatitis typeB, hepatitis type C, influenza, varicella, adenovirus, herpes simplextype I (HSV-I), herpes simplex type II (HSV-II), cattle plague,rhinovirus, echovirus, rotavirus, respiratory syncytial virus (RSV),papillomavirus, papovavirus, cytomegalovirus, echinovirus, arbovirus,huntavirus, Coxsackie virus, mumps virus, measles virus, rubella virus,polio virus, human immunodeficiency virus type I (HIV-1) and humanimmunodeficiency virus type II (HIV-II). WO 01/72779 furthermoredescribes the use of the compounds mentioned therein for GRP94modulation, where the modulated biological GRP94 activity causes animmune reaction in an individual, protein transport from theendoplasmatic reticulum, recovery from hypoxic/anoxic stress, recoveryfrom malnutrition, recovery from heat stress, or combinations thereof,and/or where the disorder is a type of cancer, an infectious disease, adisorder associated with disrupted protein transport from theendoplasmatic reticulum, a disorder associated withischaemia/reperfusion, or combinations thereof, where the disorderassociated with ischaemia/reperfusion is a consequence of cardiacarrest, asystolia and delayed ventricular arrhythmia, heart operation,cardiopulmonary bypass operation, organ transplant, spinal cord trauma,head trauma, stroke, thromboembolic stroke, haemorrhagic stroke,cerebral vasospasm, hypotonia, hypoglycaemia, status epilepticus, anepileptic fit, anxiety, schizophrenia, a neurodegenerative disorder,Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis(ALS) or neonatal stress.

Finally, WO 01/72779 describes the use of an effective amount of a GRP94protein modulator for the preparation of a medicament for changing asubsequent cellular reaction to an ischaemic state in a tissue site inan individual, by treatment of the cells at the tissue site with theGRP94 protein modulator in order that the GRP94 activity in cells isincreased to such an extent that a subsequent cellular reaction to anischaemic state is changed, where the subsequent ischaemic condition ispreferably the consequence of cardiac arrest, asystolia and delayedventricular arrhythmia, heart operation, cardiopulmonary bypassoperation, organ transplant, spinal cord trauma, head trauma, stroke,thromboembolic stroke, haemorrhagic stroke, cerebral vasospasm,hypotonia, hypoglycaemia, status epilepticus, an epileptic fit, anxiety,schizophrenia, a neurodegenerative disorder, Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS) or neonatalstress, or where the tissue site is the donor tissue for a transplant.

A. Kamal et al. in Trends in Molecular Medicine, Vol. 10 No. 6 Jun.2004, describe therapeutic and diagnostic applications of HSP90activation, inter alia for the treatment of diseases of the centralnervous system and of cardiovascular diseases.

The identification of small compounds which specifically inhibit,regulate and/or modulate HSP90 is therefore desirable and an aim of thepresent invention.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

In particular, they exhibit HSP90-inhibiting properties.

The present invention therefore relates to compounds according to theinvention as medicaments and/or medicament active compounds in thetreatment and/or prophylaxis of the said diseases and to the use ofcompounds according to the invention for the preparation of apharmaceutical for the treatment and/or prophylaxis of the said diseasesand also to a process for the treatment of the said diseases whichcomprises the administration of one or more compounds according to theinvention to a patient in need of such an administration.

The host or patient may belong to any mammal species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, where they provide a model forthe treatment of a human disease.

PRIOR ART

WO 00/53169 describes HSP90 inhibition with coumarine or a coumarinederivative.

WO 03/041643 A2 discloses HSP90-inhibiting zearalanol derivatives. OtherHSP90-inhibiting pyrazole derivatives which are substituted in the 3- or5-position by an aromatic radical are disclosed in WO 2004/050087 A1 andWO 2004/056782 A1.

WO 03/055860 A1 describes 3,4-diarylpyrazoles as HSP90 inhibitors.Purine derivatives having HSP90-inhibiting properties are disclosed inWO 02/36075 A2.

FURTHER LITERATURE

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SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R¹ denotes OH, OCH₃, OCF₃, OCHF₂, OBzl, OAc, p-methoxybenzyloxy, SH,    S(O)_(m)CH₃, SO₂NH₂, Hal, CF₃ or CH₃,-   R², R³ each, independently of one another, denote H, Hal, CN, NO₂,    A, Alk, (CH₂)_(n)Ar, (CH₂)_(n)Het, (CH₂)_(n)COOH, (CH₂)_(n)COOA,    COOAr, COOHet, CONH₂, CONHA, CONAA′, CONHAr, CONAAr, CON(Ar)₂,    CONHHet, CON(Het)₂, NH₂, NHA, NHAr, NHHet, NAA′, NHCOA, NACOA′,    NHCOAr, NHCOHet, NHCOOA, NHCOOAr, NHCOOHet, NHCONHA, NHCONHAr,    NHCONHHet, OH, OA, OAr, OHet, SH, S(O)_(m)A, S(O)_(m)Ar,    S(O)_(m)Het, SO₂NH₂, SO₂NHA, SO₂NAA′, SO₂NHAr, SO₂NAAr, SO₂NHHet,    SO₂N(Ar)₂, SO₂N(Het)₂, CONH(CH₂)_(o)Het, NH(CH₂)_(o)Het,    O(CH₂)_(o)Ar, S(O)_(m)(CH₂)_(o)Het, S(O)_(m)(CH₂)_(o)Ar,    (CH₂)_(o)CH(Ar)CH₃, CONAR¹²SO₂NA(CH₂CONAA′), SO₂NH(CH₂Ar),    SO₂NA[(CH₂)_(o)CN], SO₂NA(CH₂Ar), (CH₂)_(o)NHAr, (CH₂)_(o)NAAr,    (CH₂)_(o)OAr, (CH₂)_(o)S(O)_(m)Ar, CH═CH—Ar, CHO, COA or R¹²,-   R⁴, R⁵, R⁶ each, independently of one another, denote H, Hal, CN,    NO₂, A, Alk, (CH₂)_(n)Ar, (CH₂)_(n)Het, COOH, COOA, COOAr, COO-Het,    CONH₂, CONHA, CONAA′, CONHAr, CONAAr, CON(Ar)₂, CONHHet, CON(Het)₂,    NH₂, NHA, NHAr, NHHet, NAA′, NHCOA, NACOA′, NHCOAr, NHCOHet, NHCOOA,    NHCOOAr, NHCOOHet, NHCONHA, NHCONHAr, NHCONHHet, OH, OA, OAr, OHet,    SH, S(O)_(m)A, S(O)_(m)Ar, S(O)_(m)Het, SO₂NH₂, SO₂NHA, SO₂NAA′,    SO₂NHAr, SO₂NAAr, SO₂NHHet, SO₂N(Ar)₂, SO₂N(Het)₂, CONH(CH₂)_(o)Ar,    NHCO(CH₂)_(o)Ar, NHCO(CH₂)_(o)OA or O(CH₂)_(o)Het,-   R⁴ and R⁵ together also denote OCH₂O or OCH₂CH₂O,-   A, A′ each, independently of one another, denote unbranched or    branched alkyl having 1-10 C atoms, in which one, two or three CH₂    groups may be replaced by O, S, SO, SO₂, NH, NR⁸ and/or by —CH═CH—    groups and/or, in addition, 1-5H atoms may be replaced by F, Cl, Br    and/or R⁷,    -   Alk or cyclic alkyl having 3-7 C atoms,-   A and A′ together also denote an alkylene chain having 2, 3, 4, 5 or    6 C atoms, which may be substituted by CH₂OH, CH₂Br, CH₂NEt₂,    -   and/or in which a CH₂ group may be replaced by O, S, SO, SO₂, N,        NH, NR⁸, NCOR⁸ or NCOOR⁸,-   Alk denotes alkenyl having 2-6 C atoms,-   R⁷ denotes COOR⁹, CONR⁹R¹⁰, NR⁹R¹⁰, NHCOR⁹, NHCOOR⁹ or OR⁹,-   R⁸ denotes cycloalkyl having 3-7 C atoms,    -   cycloalkylalkylene having 4-10 C atoms,    -   Alk or    -   unbranched or branched alkyl having 1-6 C atoms, in which one,        two or three CH₂ groups may be replaced by O, S, SO, SO₂, NH        and/or, in addition, 1-5H atoms may be replaced by F and/or Cl,-   R⁹, R¹⁰ each, independently of one another, denote H or alkyl having    1-5 C atoms, in which 1-3 CH₂ groups may be replaced by O, S, SO,    SO₂, NH, NMe or NEt and/or, in addition, 1-5H atoms may be replaced    by F and/or Cl,-   R⁹ and R¹⁰ together also denote an alkylene chain having 2, 3, 4, 5    or 6 C atoms, in which a CH₂ group may be replaced by O, S, SO, SO₂,    NH, NR⁸, NCOR⁸ or NCOOR⁸,-   Ar denotes phenyl, naphthyl or biphenyl, each of which is    un-substituted or mono-, di- or trisubstituted by Hal, A, OR¹¹,    N(R¹¹)₂, NO₂, CN, phenyl, CON(R¹¹)₂, NR¹¹COA, NR¹¹CON(R¹¹)₂,    NR¹¹SO₂A, COR¹¹, NR¹¹CO(CH₂)_(n)R¹¹, SO₂N(R¹¹)₂, S(O)_(m)A,    -   —[C(R¹¹)₂]_(n)—COOR¹¹ and/or —O[C(R¹¹)₂]_(o)—COOR¹¹,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be mono-,    di- or trisubstituted by Hal, A, OR¹¹, N(R¹¹)₂, NO₂, CN, COOR¹¹,    CON(R¹¹)₂, NR¹¹COA, NR¹¹SO₂A, COR¹¹, SO₂NR¹¹, S(O)_(m)A, ═S, ═NR¹¹    and/or ═O (carbonyl oxygen),-   R¹¹ denotes H or A,-   R¹² denotes cycloalkyl having 3-7 C atoms or cycloalkylalkylene    having 4-12 C atoms,-   Hal denotes F, Cl, Br or I,-   m denotes 0, 1 or 2,-   n denotes 0, 1, 2, 3 or 4,-   o denotes 1, 2 or 3,    and pharmaceutically usable derivatives, salts, solvates and    stereoisomers thereof, including mixtures thereof in all ratios.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to Claims 1-16 and pharmaceutically usable derivatives,solvates, salts and stereoisomers thereof, characterised in that

a) a compound of the formula II

-   -   in which R¹, R² and R³ have the meanings indicated in Claim 1,        and X denotes H or methyl,        is reacted with a compound of the formula III

-   -   in which R⁴, R⁵ and R⁶ have the meanings indicated in Claim 1,        the resultant compound in which X denotes methyl is        subsequently, if desired, converted into a compound of the        formula I in which X denotes H by ether cleavage,        and/or in that one or more radical(s) R¹, R², R³, R⁴ and/or R⁵        in a compound of the formula I are converted into one or more        radical(s) R¹, R², R³, R⁴ and/or R⁵        by, for example,

-   i) reducing a nitro group to an amino group,

-   ii) hydrolysing an ester group to a carboxyl group,

-   iii) converting an amino group into an alkylated amine by reductive    amination,

-   iv) converting a carboxyl group into a sulfonamidocarbonyl group,

-   v) converting an acid chloride into an amide,    and/or

A base or acid of the formula I is converted into one of its salts.

The invention also relates to the stereoisomers (E, Z isomers) and thehydrates and solvates of these compounds. Solvates of the compounds aretaken to mean adductions of inert solvent molecules onto the compoundswhich form owing to their mutual attractive force. Solvates are, forexample, mono- or dihydrates or alcoholates.

Pharmaceutically usable derivatives are taken to mean, for example, thesalts of the compounds according to the invention and also so-calledprodrug compounds.

Prodrug derivatives are taken to mean compounds of the formula I whichhave been modified with, for example, alkyl or acyl groups, sugars oroligopeptides and which are rapidly cleaved in the organism to give theeffective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” means the amount of a medicament orpharmaceutical active compound which causes a biological or medicalresponse which is sought or desired, for example, by a researcher orphysician in a tissue, system, animal or human.

In addition, the expression “therapeutically effective amount” means anamount which, compared with a corresponding subject who has not receivedthis amount, has the following consequence: improved healing treatment,healing, prevention or elimination of a disease, a disease picture, adisease state, a complaint, a disorder or of side effects or also thereduction in the progress of a disease, a complaint or a disorder.

The term “therapeutically effective amount” also encompasses the amountswhich are effective for increasing normal physiological function.

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

For all radicals which occur more than once, their meanings areindependent of one another.

Above and below, the radicals and parameters R¹, R², R³, R⁴ and R⁵ havethe meanings indicated for the formula I, unless expressly indicatedotherwise.

A or A′ preferably denotes alkyl, is unbranched (linear) or branched,and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A or A′ particularlypreferably denotes denotes methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl. A or A′ veryparticularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms,preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or1,1,1-trifluoroethyl.

A or A′ also denotes cycloalkyl. Cycloalkyl preferably denotescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A or A′ also denotes Alk. Alk denotes alkenyl having 2-6 C atoms, suchas, for example, vinyl or propenyl.

Cycloalkylalkylene denotes, for example, cyclopropylmethyl orcyclopentylmethyl.

Ac denotes acetyl, Bzl denotes benzyl, Ms denotes —SO₂CH₃.

Selectfluor/F-TEDA-BF4/1(1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octanebis(tetra-fluoroborate))=

PdCl₂(dppf) denotes[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II):

R¹ preferably denotes OH, OCH₃ or SH, particularly preferably OH orOCH₃, furthermore also OCF₃, OCHF₂.

R², R³ preferably each, independently of one another, denote H, Hal, A,(CH₂)_(n)Ar, (CH₂)_(n)Het, (CH₂)_(n)COOH, (CH₂)_(n)COOA, CONH₂, CONHA,CONAA′, CONHAr, CONHHet, NH₂, NHA, NHAr, NHHet, NAA′, S(O)_(m)A,S(O)_(m)Ar, SO₂NH₂, SO₂NHA, SO₂NAA′, SO₂NHAr, SO₂NAAr, SO₂NHHet,CONH(CH₂)_(o)Het, NH(CH₂)_(o)Het, O(CH₂)_(o)Ar, S(O)_(m)(CH₂)_(o)Het,S(O)_(m)(CH₂)_(o)Ar, (CH₂)_(o)CH(Ar)CH₃, CONAR², SO₂NA(CH₂CONAA′),SO₂NH(CH₂Ar), SO₂NA[(CH₂)_(o)CN], SO₂NA(CH₂Ar), (CH₂)_(o)NHAr,(CH₂)_(o)NAAr, (CH₂)_(o)OAr, (CH₂)_(o)S(O)_(m)Ar, CH═CH—Ar or R², whereR³ particularly preferably denotes H.

R² particularly preferably denotes H; Hal, such as, for example, Cl, Bror I; A, such as, for example, methyl or ethyl; SO₂NAA′, CONAA′, SO₂NHA,where A, A′ each, independently of one another, denotes unbranched orbranched alkyl having 1-6 C atoms, in which, in addition, 1-5H atoms maybe replaced by F, Cl and/or Br,

or cyclic alkyl having 3-7 C atoms,

and where A and A′ together also denote an alkylene chain having 3, 4, 5or 6 C atoms, which may be substituted by CH₂OH, CH₂Br or CH₂NEt₂,and/or in which a CH₂ group may be replaced by O, N, NH or NA;

R² furthermore particularly preferably denotes SO₂NH₂,fluorophenylaminosulfonyl, phenylaminosulfonyl, benzylaminosulfonyl,pyridylaminosulfonyl, phenylthio, benzyl, phenylsulfonyl, phenyl,2-phenylethyl, 2-(pyridyl)ethyl, fluorophenyl, 2-phenylvinyl,2-carboxyethyl, 2-(methoxycarbonyl)ethyl, 2-(fluorophenyl)ethyl,SO₂N(CH₂CH₂OH, CH₂CH₂Br), SO₂NA(CH₂CH₂CN), SO₂NA(CH₂CH₂Br),SO₂NA(CH₂CONAA′) or SO₂NA(CH₂phenyl).

R⁴, R⁵, R⁶ preferably each, independently of one another, denote H, Hal,CN, NO₂, A, (CH₂)_(n)Ar, COOH, COOA, CONH₂, CONHA, CONAA′, CONHAr, NH₂,NHA, NAA′, NHCOA, NHCOAr, NHCOHet, OH, OA, SO₂NH₂, SO₂NHA, SO₂NAA′,CONH(CH₂)_(o)Ar, NHCO(CH₂)_(o)Ar, NHCO(CH₂)_(o)OA or O(CH₂)_(o)Het.

R⁴ particularly preferably denotes H.

R⁵ particularly preferably denotes H, F, Cl, CN or A, such as, forexample, methyl, ethyl or trifluoromethyl.

R⁶ particularly preferably denotes H, NHCOA, NH₂, NO₂, COOH, Fl, Cl, Br,A, OA, OH, CN, SO₂NH₂, COOA,4-[2-(4-methylpiperazin-1-yl)ethoxy]-phenyl, benzyl, benzoylamino,benzylcarbonylamino, pyridylcarbonylamino or methoxyethylcarbonylamino,

where A preferably denotes unbranched or branched alkyl having 1-6 Catoms, in which 1-5H atoms may be replaced by F, Cl and/or Br.

R⁷preferably denotes COOR⁹, such as, for example, COOH or COOCH₃;CONR⁹R¹⁰, such as, for example, CONH₂; NR⁹R¹⁰, such as, for example,amino, methylamino or dimethylamino; NHCOR⁹, NHCOOR⁹ or OR⁹, such as,for example, hydroxyl or methoxy;

R⁸ preferably denotes cyclopentyl, cyclohexyl, methyl, ethyl, propyl orbutyl.

R⁹, R¹⁰ preferably each, independently of one another, denote H or alkylhaving 1-5 C atoms, in which 1-5H atoms may be replaced by F and/or Cl.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p- aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p- chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-cyanophenyl, o-, m- or p-ureidophenyl, o-, m- or p-formylphenyl,o-, m- or p-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- orp-carboxyphenyl, o-, m- or p-carboxymethylphenyl, o-, m- orp-carboxymethoxyphenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl,3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-,2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl,2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar preferably denotes, for example, phenyl which is unsubstituted ormono-, di- or trisubstituted by Hal, A, OR¹¹, N(R¹¹)₂, NR¹¹COA,NR¹¹CO(CH₂)_(o)R¹¹, and/or —[C(R¹¹)₂]_(n)—COOR¹¹, where R¹¹ denotes H orA, such as, for example, methyl. Ar very particularly preferably denotesphenyl which is unsubstituted or mono-, di- or trisubstituted by Haland/or A.

Het denotes, irrespective of further substitutions, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, 4- or 5-yl, 1,2,4-triazol-1-, 3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl,1,3,4-thiadiazol-2- or 5-yl, 1,2,4-thiadiazol-3- or 5-yl,1,2,3-thiadiazol-4- or 5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-,4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-, 4-, 5-,6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl,3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or 5-yl or2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals may also be partially or fully hydrogenated.Het can thus also denote, for example, 2,3-dihydro-2-, 3-, 4- or5-furyl, 2,5-dihydro-2-, 3-, 4- or 5-furyl, tetrahydro-2- or 3-furyl,1,3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, 2-, 3-,4- or 5-pyrrolyl, 2,5-dihydro-1-, 2-, 3-, 4- or 5-pyrrolyl, 1-, 2- or3-pyrrolidinyl, tetrahydro-1-, -2- or 4-imidazolyl, 2,3-dihydro-1-, 2-,3-, 4- or 5-pyrazolyl, tetrahydro-1-, 3- or 4-pyrazolyl, 1,4-dihydro-1-,2-, 3- or 4-pyridyl, 1,2,3,4-tetrahydro-1-, 2-, 3-, 4-, 5- or 6-pyridyl,1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, 3-or 4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-,-4- or 5-yl, hexahydro-1-, 3-or 4-pyridazinyl, hexahydro-1-, 2-, 4- or 5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, 2-, 3-, 4-, 5-, -6-, 7- or8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-, 3-, 4-, 5-, 6-, 7- or8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or 7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het preferably denotes a monocyclic saturated, unsaturated or aromaticheterocycle having 1 to 2 N and/or O atoms, which may be un-substitutedor mono-, di- or trisubstituted by A, Hal, OH and/or OA.

Het particularly preferably denotes a monocyclic saturated heterocyclehaving 1 to 2 N and/or O atoms, which may be unsubstituted or mono- ordisubstituted by A.

In a further embodiment, Het very particularly preferably denotespyrrolidinyl, piperidinyl, morpholinyl or piperazinyl.

In a further embodiment, Het particularly preferably denotes furyl,thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl,thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl orpiperazinyl, each of which is un-substituted or mono-, di- ortrisubstituted by A, Hal, OH and/or OA.

In a very particularly preferred embodiment, Het denotes pyridyl,piperidinyl or piperazinyl.

The compounds of the formula I may have one or more chiral centres andtherefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Particular preference is given to compounds of the formula I selectedfrom the group

-   5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,-   5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,-   5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,-   5-[5-(N-isopropyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,-   5-{5-[2-(2-fluorophenyl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,-   5-[5-(N-propyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,-   5-(2,4-dihydroxy-5-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazole,-   5-(2,4-dihydroxy-5-chlorophenyl)-1-(2-fluorophenyl)-1H-pyrazole,-   5-(2,4-dihydroxy-5-bromophenyl)-1-(2-ethylphenyl)-1H-pyrazole,-   5-[5-(N-propyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-{4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-1H-pyrazole,    and pharmaceutically usable derivatives, solvates, salts and    stereoisomers thereof, including mixtures thereof in all ratios.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to II, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R¹ denotes OH, OCH₃ or SH;-   in Ib R², R³ each, independently of one another, denote H, Hal, A,    (CH₂)_(n)Ar, (CH₂)_(n)Het, (CH₂)_(n)COOH, (CH₂)_(n)COOA, CONH₂,    CONHA, CONAA′, CONHAr, CONHHet, NH₂, NHA, NHAr, NHHet, NAA′,    S(O)_(m)A, S(O)_(m)Ar, SO₂NH₂, SO₂NHA, SO₂NAA′, SO₂NHAr, SO₂NAAr,    SO₂NHHet, CONH(CH₂)_(o)Het, NH(CH₂)_(o)Het, O(CH₂)_(o)Ar,    S(O)_(m)(CH₂)_(o)Het, S(O)_(m)(CH₂)_(o)Ar, (CH₂)_(o)CH(Ar)CH₃,    CONAR², SO₂NA(CH₂CONAA′), SO₂NH(CH₂Ar), SO₂NA[(CH₂)_(o)CN],    SO₂NA(CH₂Ar), (CH₂)_(o)NHAr, (CH₂)_(o)NAAr, (CH₂)_(o)OAr,    (CH₂)_(o)S(O)_(m)Ar or R¹²;-   in Ic R⁴, R⁵, R⁶ each, independently of one another, denote H, Hal,    CN, NO₂, A, (CH₂)_(n)Ar, COOH, COOA, CONH₂, CONHA, CONAA′, CONHAr,    NH₂, NHA, NAA′, NHCOA, NHCOAr, NHCOHet, OH, OA, SO₂NH₂, SO₂NHA,    SO₂NAA′, CONH(CH₂)_(o)Ar, NHCO(CH₂)_(o)Ar, NHCO(CH₂)_(o)OA or    O(CH₂)_(o)Het;-   in Id A, A′ each, independently of one another, denote unbranched or    branched alkyl having 1-10 C atoms, in which one, two or three CH₂    groups may be replaced by O, S, SO, SO₂, NH, NR⁸ and/or by —CH═CH—    groups and/or, in addition, 1-5H atoms may be replaced by F, Cl, Br    and/or R⁷, Alk or cyclic alkyl having 3-7 C atoms,    -   A and A′ together also denote an alkylene chain having 2, 3, 4,        5 or 6 C atoms, which may be substituted by CH₂OH, CH₂Br or        CH₂NEt₂, and/or in which a CH₂ group may be replaced by O, N, NH        or NR⁸;-   in Ie A, A′ each, independently of one another, denote unbranched or    branched alkyl having 1-6 C atoms, in which one, two or three CH₂    groups may be replaced by O, S, SO, SO₂, NH and/or by —CH═CH— groups    and/or, in addition, 1-5H atoms may be replaced by F, Cl and/or Br,    -   Alk or cyclic alkyl having 3-7 C atoms;-   in If R⁷ denotes COOR⁹, CONR⁹R¹⁰, NR⁹R¹⁰, NHCOR⁹, NHCOOR⁹ or OR⁹;-   in Ig R⁸ denotes unbranched or branched alkyl having 1-6 C atoms;-   in Ih R⁹, R¹⁰ each, independently of one another, denote H or alkyl    having 1-5 C atoms, in which 1-5H atoms may be replaced by F and/or    Cl;-   in Ii A, A′ each, independently of one another, denote unbranched or    branched alkyl having 1-6 C atoms, in which 1-5H atoms may be    replaced by F, Cl and/or Br, or cyclic alkyl having 3-7 C atoms;-   in Ij Ar denotes phenyl which is unsubstituted or mono-, di- or    trisubstituted by Hal, A, OR¹¹, N(R¹¹)₂, NR¹¹COA,    NR¹¹CO(CH₂)_(n)R¹¹, and/or —[C(R¹¹)₂]_(n)—COOR¹¹;-   in Ik Het denotes a mono- or bicyclic saturated or aromatic    heterocycle having 1 to 2 N and/or O atoms, which may be mono- or    disubstituted by A;-   in Il R¹ denotes OH, OCH₃ or SH,    -   R², R³ each, independently of one another, denote H, Hal, A,        (CH₂)_(n)Ar, (CH₂)_(n)Het, (CH₂)_(n)COOH, (CH₂)_(n)COOA, CONH₂,        CONHA, CONAA′, CONHAr, CONHHet, NH₂, NHA, NHAr, NHHet, NAA′,        S(O)_(m)A, S(O)_(m)Ar, SO₂NH₂, SO₂NHA, SO₂NAA′, SO₂NHAr,        SO₂NAAr, SO₂NHHet, CONH(CH₂)_(o)Het, NH(CH₂)_(o)Het,        O(CH₂)_(o)Ar, S(O)_(m)(CH₂)_(o)Het, S(O)_(m)(CH₂)_(o)Ar,        (CH₂)_(o)CH(Ar)CH₃, CONAR¹², SO₂NA(CH₂CONAA′), SO₂NH(CH₂Ar),        SO₂NA[(CH₂)_(o)CN], SO₂NA(CH₂Ar), (CH₂)_(o)NHAr, (CH₂)_(o)NAAr,        (CH₂)_(o)OAr, (CH₂)_(o)S(O)_(m)Ar or R¹²,    -   R⁴, R⁵, R⁶ each, independently of one another, denote H, Hal,        CN, NO₂, A, (CH₂)_(n)Ar, COOH, COOA, CONH₂, CONHA, CONAA′,        CONHAr, NH₂, NHA, NAA′, NHCOA, NHCOAr, NHCOHet, OH, OA, SO₂NH₂,        SO₂NHA, SO₂NAA′, CONH(CH₂)_(o)Ar, NHCO(CH₂)_(o)Ar,        NHCO(CH₂)_(o)OA or O(CH₂)_(o)Het,    -   R⁴ and R⁵ together also denote OCH₂O or OCH₂CH₂O,    -   A, A′ each, independently of one another, denote unbranched or        branched alkyl having 1-10 C atoms, in which one, two or three        CH₂ groups may be replaced by O, S, SO, SO₂, NH, NR⁸ and/or by        —CH═CH— groups and/or, in addition, 1-5H atoms may be replaced        by F, Cl, Br and/or R⁷,        -   Alk or cyclic alkyl having 3-7 C atoms,    -   A and A′ together also denote an alkylene chain having 2, 3, 4,        5 or 6 C atoms, which may be substituted by CH₂OH, CH₂Br or        CH₂NEt₂,        -   and/or in which a CH₂ group may be replaced by O, N, NH or            NR⁸,    -   R⁷ denotes COOR⁹, CONR⁹R¹⁰, NR⁹R¹⁰, NHCOR⁹, NHCOOR⁹ or OR⁹,    -   R⁸ denotes unbranched or branched alkyl having 1-6 C atoms,    -   R⁹, R¹⁰ each, independently of one another, denote H or alkyl        having 1-5 C atoms, in which 1-5H atoms may be replaced by F        and/or Cl,    -   Ar denotes phenyl which is unsubstituted or mono-, di- or        trisubstituted by Hal, A, OR¹¹, N(R¹¹)₂, NR¹¹COA,        NR¹¹CO(CH₂)_(o)R¹¹, and/or        -   —[C(R¹¹)₂]_(n)—COOR¹¹,    -   Het denotes a mono- or bicyclic saturated or aromatic        heterocycle having 1 to 2 N and/or O atoms, which may be mono-        or disubstituted by A,    -   R¹¹ denotes H or A,    -   R¹² denotes cycloalkyl having. 3-7 C atoms or cycloalkylalkylene        having 4-12 C atoms,    -   Hal denotes F, Cl, Br or I,    -   m denotes 0, 1 or 2,    -   n denotes 0, 1, 2, 3 or 4,    -   o denotes 1, 2 or 3;        and pharmaceutically usable derivatives, solvates, salts and        stereoisomers thereof, including mixtures thereof in all ratios.

The compounds according to the invention and also the starting materialsfor their preparation are, in addition, prepared by methods known perse, as described in the literature (for example in the standard works,such as Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use may also be made here of variants known per se which are notmentioned here in greater detail.

If desired, the starting materials can also be formed in situ by notisolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds according to the invention.

The starting compounds are generally known. If they are novel, however,they can be prepared by methods known per se.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II with a hydrazide of the formula Ill. Thereaction generally gives the 1,5-diphenylpyrazole derivative. The1,3-diphenyl derivative may form as by-product.

The reaction is carried out by methods which are known to the personskilled in the art.

Reaction is firstly carried out in a suitable solvent.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particularly preferred solvents are alcohols, such as, for example,isopropanol or ethanol.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 110°, in particular between about 20°and about 100°.

In the resultant compound of the formula I

in which X denotes H or methyl,the ether cleavage is optionally carried out by methods which are knownto the person skilled in the art.

The reaction is carried out in a suitable solvent, as indicated above,preferably by addition of boron tribromide.

The reaction is particularly preferably carried out in dichloromethaneat a reaction temperature between about −30° and 50°, normally between−20° and 20°, in particular between about −15° and about 0°.

This gives compounds of the formula I in which X denotes H.

It is furthermore possible to convert a compound of the formula I intoanother compound of the formula I by converting one or more radical(s)R¹, R², R³, R⁴ and/or R⁵ into one or more other radicals R¹, R², R³, R⁴and/or R⁵, for example by reducing nitro groups to amino groups, forexample by hydrogenation on Raney nickel or Pd/carbon in an inertsolvent, such as methanol or ethanol, and/or

converting an ester group into a carboxyl group and/or converting anamino group into an alkylated amine by reductive amination and/oresterifying carboxyl groups by reaction with alcohols and/or convertingacid chlorides into an acid amide by reaction with an amine.

Furthermore, free amino groups can be acylated in a conventional mannerusing an acid chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide, advantageously in an inert solvent, such asdichloromethane or THF, and/or in the presence of a base, such astriethylamine or pyridine, at temperatures between −60 and +30°.

The invention also relates to intermediate compounds of the formula II

in which

-   R¹ denotes OCH₃, OBzl, OAc, p-methoxybenzyloxy or 1,-   R², R³ denote H-   R⁴, R⁵, R⁶ each, independently of one another, denote H, Hal, CN,    NO₂, A, COOH, COOA, NH₂, OH, OA or SO₂NH₂,-   X denotes CH₃, Bzl, Ac or p-methoxybenzyl,-   A denotes unbranched or branched alkyl having 1-6 C atoms, in which    1-5H atoms may be replaced by F and/or Cl,    -   or cyclic alkyl having 3-7 C atoms,        and salts thereof.

Alternative processes for the preparation of compounds of the formula I:

1. Arylation of pyrazoles using substituted phenyl iodides

Literature:

Fr. Demande, 2840303, 05 Dec. 2003;

U.S. Pat. Appl. Publ., 2003236413, 25 Dec. 2003;

3. Other processes for the preparation of 1,5-diarylpyrazoles aredescribed by

a) Zhu, Jiuxiang; Song, Xueqin; Lin, Ho-Pi; Young, Donn C.; Yan, Shunqi;Marquez, Victor E.; Chen, Ching-Shih. College of Pharmacy, Division ofMedicinal Chemistry and Pharmacognosy, The Ohio State University,Columbus, Ohio, USA. Journal of the National Cancer Institute (2002),94(23), 1745-1757.b) Pal, Manojit; Madan, Manjula; Padakanti, Srinivas; Pattabiraman,Vijaya R.; Kalleda, Srinivas; Vanguri, Akhila; Mullangi, Ramesh; Mamidi,N. V. S. Rao; Casturi, Seshagiri R.; Malde, Alpeshkumar; Gopalakrishnan,B.; Yeleswarapu, Koteswar R. Discovery-Chemistry and Discovery-Biology,Dr Reddy's Laboratories Ltd., Hyderabad, India. Journal of MedicinalChemistry (2003), 46(19).

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethane-sulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active compound which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active compound compared withthe free form of the active compound or any other salt form of theactive compound used earlier. The pharmaceutically acceptable salt formof the active compound can also provide this active compound for thefirst time with a desired pharmacokinetic property which it did not haveearlier and can even have a positive influence on the pharmacodynamicsof this active compound with respect to its therapeutic efficacy in thebody.

Compounds of the formula I according to the invention may be chiralowing to their molecular structure and may accordingly occur in variousenantiomeric forms. They can therefore exist in racemic or in opticallyactive form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/ acetonitrile, for example in theratio 82:15:3.

The invention furthermore relates to the use of the compounds and/orphysiologically acceptable salts thereof for the preparation of amedicament (pharmaceutical composition), in particular by non-chemicalmethods. They can be converted into a suitable dosage form here togetherwith at least one solid, liquid and/or semi-liquid excipient or adjuvantand, if desired, in combination with one or more further activecompounds.

The invention furthermore relates to medicaments comprising at least onecompound according to the invention and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active compound perdosage unit. Such a unit can comprise, for example, 0.1 mg to 3 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the disease conditiontreated, the method of administration and the age, weight and conditionof the patient, or pharmaceutical formulations can be administered inthe form of dosage units which comprise a predetermined amount of activecompound per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active compound. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active compound with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbent, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape which arebroken up to form granules. The granules can be lubricated by additionof stearic acid, a stearate salt, talc or mineral oil in order toprevent sticking to the tablet casting moulds. The lubricated mixture isthen pressed to give tablets. The compounds according to the inventioncan also be combined with a free-flowing inert excipient and thenpressed directly to give tablets without carrying out the granulation ordry-pressing steps. A transparent or opaque protective layer consistingof a shellac sealing layer, a layer of sugar or polymer material and agloss layer of wax may be present. Dyes can be added to these coatingsin order to be able to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can bepre-pared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compounds. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds according to the invention and salts, solvates andphysiologically functional derivatives thereof can also be administeredin the form of liposome delivery systems, such as, for example, smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from various phospholipids, such as,for example, cholesterol, stearylamine or phosphatidylcholines.

The compounds according to the invention and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds can also be coupled to solublepolymers as targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active compoundcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activecompound can be employed either with a paraffinic or a water-misciblecream base.

Alternatively, the active compound can be formulated to give a creamwith an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active compound is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary.

Injection solutions and suspensions prepared in accordance with therecipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the presentinvention depends on a number of factors, including, for example, theage and weight of the human or animal, the precise disease conditionwhich requires treatment, and its severity, the nature of theformulation and the method of administration, and is ultimatelydetermined by the treating doctor or vet. However, an effective amountof a compound according to the invention is generally in the range from0.1 to 100 mg/kg of body weight of the recipient (mammal) per day andparticularly typically in the range from 1 to 10 mg/kg of body weightper day. Thus, the actual amount per day for an adult mammal weighing 70kg is usually between 70 and 700 mg, where this amount can beadministered as an individual dose per day or usually in a series ofpart-doses (such as, for example, two, three, four, five or six) perday, so that the total daily dose is the same. An effective amount of asalt or solvate or of a physiologically functional derivative thereofcan be determined as the fraction of the effective amount of thecompound according to the invention per se. It can be assumed thatsimilar doses are suitable for the treatment of other conditionsmentioned above.

The invention furthermore relates to medicaments comprising at least onecompound according to the invention and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and at least one further medicament activecompound.

Further medicament active compounds are preferably chemotherapeuticagents, in particular those which inhibit angiogenesis and thus inhibitthe growth and spread of tumour cells; preference is given here to VEGFreceptor inhibitors, including robozymes and antisense which aredirected to VEGF receptors, and angiostatin and endostatin.

Examples of antineoplastic agents which can be used in combination withthe compounds according to the invention generally include alkylatingagents, antimetabolites; epidophyllotoxin; an antineoplastic enzyme; atopoisomerase inhibitor; procarbazin; mitoxantron or platinumcoordination complexes.

Antineoplastic agents are preferably selected from the followingclasses: anthracyclins, vinca medicaments, mitomycins, bleomycins,cytotoxic nucleosides, epothilones, discodermolides, pteridines,diynenes and podophyllotoxins.

Particular preference is given in the said classes to, for example,carminomycin, daunorubicin, aminopterin, methotrexate, methopterin,dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil,6-mercaptopurine, gemcitabine, cytosinarabinoside, podophyllotoxin orpodophyllotoxin derivatives, such as, for example, etoposide, etoposidephosphate or teniposide, melphalan, vinblastine, vincristine,leurosidine, vindesine, leurosine and paclitaxel. Other preferredantineoplastic agents are selected from the group estramustine,carboplatin, cyclophosphamide, bleomycin, gemcitabine, ifosamide,melphalan, hexamethylmelamine, thiotepa, cytarabin, idatrexate,trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11,topotecan, arabinosylcytosine, bicalutamide, flutamide, leuprolide,pyridobenzoindole derivatives, interferons and interleukins.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound according to the invention    and/or pharmaceutically usable derivatives, solvates and    stereoisomers thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active compound.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound according tothe invention and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active compound in dissolved orlyophilised form.

Use

The present compounds are suitable as pharmaceutical active compoundsfor mammals, in particular for humans, in the treatment of diseases inwhich HSP90 plays a role.

The invention thus relates to the use of compounds according to Claim 1and to pharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios, for the preparation of amedicament for the treatment of diseases in which the inhibition,regulation and/or modulation of HSP90 plays a role.

Preference is given here to SGK.

Preference is given to the use of compounds according to Claim 1 andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, for the preparation of amedicament for the treatment of tumour diseases, for examplefibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumour,leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, syringocarcinoma, sebaceous cellcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinomas, bone marrow carcinoma, bronchogenic carcinoma,renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonic carcinoma, Wilm's tumour, cervical cancer,testicular tumour, lung carcinoma, small-cell lung carcinoma, bladdercarcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, haemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma, leukaemia, lymphoma, multiple myeloma, Waldenström'smacroglobulinaemia and heavy-chain disease;

viral diseases, where the viral pathogen is selected from the groupconsisting of hepatitis type A, hepatitis type B, hepatitis type C,influenza, varicella, adenovirus, herpes simplex type I (HSV-I), herpessimplex type II (HSV-II), cattle plague, rhinovirus, echovirus,rotavirus, respiratory syncytial virus (RSV), papillomavirus,papovavirus, cytomegalovirus, echinovirus, arbovirus, huntavirus,Coxsackie virus, mumps virus, measles virus, rubella virus, polio virus,human immunodeficiency virus type I (HIV-I) and human immunodeficiencyvirus type II (HIV-II); for immune suppression in transplants;inflammation-induced diseases, such as rheumatoid arthritis, asthma,multiple sclerosis, type 1 diabetes, lupus erythematosus, psoriasis andinflammatory bowel disease; cystic fibrosis; diseases associated withangiogenesis, such as, for example, diabetic retinopathy, haemangioma,endometriosis, tumour angiogenesis; infectious diseases; autoimmunediseases; ischaemia; promotion of nerve regeneration; fibrogeneticdiseases, such as, for example, dermatoscierosis, polymyositis, systemiclupus, cirrhosis of the liver, keloid formation, interstitial nephritisand pulmonary fibrosis;

The compounds according to the invention can inhibit, in particular, thegrowth of cancer, tumour cells and tumour metastases and are thereforesuitable for tumour therapy.

The present invention furthermore encompasses the use of the compoundsaccording to Claim 1 according to the invention and/or physiologicallyacceptable salts and solvates thereof for the preparation of amedicament for the protection of normal cells against toxicity caused bychemotherapy, and for the treatment of diseases in which incorrectprotein folding or aggregation is a principal causal factor, such as,for example, scrapie, Creutzfeldt-Jakob disease, Huntington's orAlzheimer's.

The invention also relates to the use of the compounds according toClaim 1 according to the invention and/or physiologically acceptablesalts and solvates thereof for the preparation of a medicament for thetreatment of diseases of the central nervous system, of cardiovasculardiseases and cachexia.

In a further embodiment, the invention also relates to the use of thecompounds according to Claim 1 according to the invention and/orphysiologically acceptable salts and solvates thereof for thepreparation of a medicament for HSP90 modulation, where the modulatedbiological HSP90 activity causes an immune reaction in an individual,protein transport from the endoplasmatic reticulum, recovery fromhypoxic/anoxic stress, recovery from malnutrition, recovery from heatstress, or combinations thereof, and/or where the disorder is a type ofcancer, an infectious disease, a disorder associated with disruptedprotein transport from the endoplasmatic reticulum, a disorderassociated with ischaemia/reperfusion, or combinations thereof, wherethe disorder associated with ischaemia/reperfusion is a consequence ofcardiac arrest, asystolia and delayed ventricular arrhythmia, heartoperation, cardiopulmonary bypass operation, organ transplant, spinalcord trauma, head trauma, stroke, thromboembolic stroke, haemorrhagicstroke, cerebral vasospasm, hypotonia, hypoglycaemia, statusepilepticus, an epileptic fit, anxiety, schizophrenia, aneurodegenerative disorder, Alzheimer's disease, Huntington's disease,amyotrophic lateral sclerosis (ALS) or neonatal stress.

In a further embodiment, the invention also relates to the use of thecompounds according to Claim 1 according to the invention and/orphysiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment of ischaemia as aconsequence of cardiac arrest, asystolia and delayed ventriculararrhythmia, heart operation, cardiopulmonary bypass operation, organtransplant, spinal cord trauma, head trauma, stroke, thromboembolicstroke, haemorrhagic stroke, cerebral vasospasm, hypotonia,hypoglycaemia, status epilepticus, an epileptic fit, anxiety,schizophrenia, a neurodegenerative disorder, Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS) or neonatalstress.

Test Method for the Measurement of HSP90 Inhibitors

The binding of geldanamycin or 17-allylamino-17-demethoxygeldanamycin(17AAG) to HSP90 and competitive inhibition thereof can be utilised inorder to determine the inhibitory activity of the compounds according tothe invention (Carreras et al. 2003, Chiosis et al. 2002).

In the specific case, a radioligand filter binding test is used. Theradioligand used here is tritium-labelled 17-allylaminogeldanamycin,[3H]17AAG. This filter binding test allows a targeted search forinhibitors which interfere with the ATP binding site.

Material

Recombinant human HSP90a (E. coli expressed, 95% purity);

[3H]17AAG (17-allylaminogeldanamycin, [allylamino-2,3-³H. Specificactivity: 1.11×10¹² Bq/mmol (Moravek, Mont.-1717);

HEPES filter buffer (50 mM HEPES, pH 7.0, 5 mM MgCl2, BSA 0.01%)Multiscreen FB (1 μm) filter plate (Millipore, MAFBNOB 50).

Method

The 96-well microtitre filter plates are firstly irrigated and coatedwith 0.1% of polyethylenimine.

The test is carried out under the following conditions:

Reaction temperature 22° C.

Reaction time: 30 min., shaking at 800 rpm

Test volume: 50 μl

Final concentrations:

50 mM HEPES HCl, pH 7.0, 5 mM MgCl2, 0.01% (w/v) BSA

HSP90:1.5 μg/assay

[3H]17AAG: 0.08 μM.

At the end of the reaction, the supernatant in the filter plate isremoved by suction with the aid of a vacuum manifold (MultiscreenSeparation System, Millipore), and the filter is washed twice.

The filter plates are then measured in a beta counter (Microbeta,Wallac) with scintillator (Microscint 20, Packard).

“% of control” is determined from the “counts per minutes” values andthe IC-50 value of a compound is calculated therefrom.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: if necessary, water is added,the pH is adjusted, if necessary, to between 2 and 10, depending on theconstitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the product is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent: ethyl acetate/methanol 9:1.

LC-MS Conditions

HP 1100 series Hewlett Packard System having the following features: ionsource: electrospray (positive mode); scan: 100-1000 m/e; fragmentationvoltage: 60 V; gas temperature: 300° C., DAD: 220 nm.

Flow rate: 2.4 ml/min. The splitter used reduced the flow rate for theMS to 0.75 ml/min. after the DAD.

Column: Chromolith SpeedROD RP-18e 50-4.6

Solvent: LiChrosolv quality from Merck KGaA

Solvent A: H2O (0.01% of TFA)

Solvent B: ACN (0.008% of TFA)

Gradient:

20% of B→100% of B: 0 min to 2.8 min

100% of B: 2.8 min to 3.3 min

100% of B→20% of B: 3.3 min to 4 min

The retention times and M+H⁺ data indicated in the following examplesare the measurement results of the LC-MS measurements.

EXAMPLE 1 Preparation of5-(2-hydroxy-4-methoxyphenyl)-1-(3-nitrophenyl)-1H-pyrazole (“A1”) 1.Reaction of resorcinol with glacial acetic acid in the presence of borontrifluoride etherate gives 2,4-dihydroxyacetophenone. 2.N,N-dimethylformamide dimethyl acetal (DMA) is added to a solution of2,4-dihydroxyacetophenone in dimethylformamide (DMF), and the mixture isrefluxed for 24 hours on a water separator.

Removal of the solvent and conventional work-up gives (“1”)

3. A solution of 500 mg of “1” and 428.5 mg of (3-nitrophenyl)hydrazinehydrochloride in 20 ml of ethanol is refluxed for 16 hours. Removal ofthe solvent and conventional work-up gives “A1”, retention time [min]1.776, M+H⁺[m/e] 312.30;

The following compounds are obtained analogously

-   5-(2-hydroxy-4-methyl-5-chlorophenyl)-1-phenyl-1H-pyrazole,-   5-(2-hydroxy-4-fluorophenyl)-1-(3,5-dichlorophenyl)-1H-pyrazole,    retention time [min] 2.251, M+H⁺[m/e] 324.15;-   5-(2-hydroxy-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1H-pyrazole,    retention time [min] 1.843, M+H⁺[m/e] 324.15;-   5-(2-hydroxy-4-fluorophenyl)-1-(2-chloro-5-trifluoromethylphenyl)-1H-pyrazole,    retention time [min] 2.068, M+H⁺[m/e] 357.71;-   5-(2-hydroxy-4-fluorophenyl)-1-(2-ethylphenyl)-1H-pyrazole,    retention time [min] 1.917, M+H⁺[m/e] 283.32;-   5-(2-hydroxy-4-fluorophenyl)-1-(3-methoxyphenyl)-1H-pyrazole,    retention time [min] 1.755, M+H⁺[m/e] 285.29;-   5-(2-hydroxy-4-fluorophenyl)-1-(3-cyanophenyl)-1H-pyrazole,    retention time [min] 1.731, M+H⁺[m/e] 280.27;-   5-(2-hydroxy-4-fluorophenyl)-1-(3-trifluoromethylphenyl)-1H-pyrazole,    retention time [min] 2.067, M+H⁺[m/e] 323.26;-   5-(2-hydroxy-4-fluorophenyl)-1-(3-chlorophenyl)-1H-pyrazole,    retention time [min] 1.965, M+H⁺[m/e] 289.71;-   5-(2-hydroxy-4-fluorophenyl)-1-(3-fluorophenyl)-1H-pyrazole,    retention time [min] 1.823, M+H⁺[m/e] 273.25;-   5-(2-hydroxy-4-fluorophenyl)-1-phenyl-1H-pyrazole, retention time    [min] 1.729, M+H⁺[m/e] 255.26;-   5-(2-hydroxy-4-fluorophenyl)-1-(4-trifluoromethylphenyl)-1H-pyrazole,    retention time [min] 2.090, M+H⁺[m/e] 323.26;-   5-(2-hydroxy-4-fluorophenyl)-1-(4-chlorophenyl)-1H-pyrazole,    retention time [min] 1.962, M+H⁺[m/e] 289.71;-   5-(2-hydroxy-4-fluorophenyl)-1-(4-aminosulfonylphenyl)-1H-pyrazole,    retention time [min] 1.376, M+H⁺[m/e] 334.34;-   5-(2-hydroxy-4-fluorophenyl)-1-(4-carboxyphenyl)-1H-pyrazole,    retention time [min] 1.472, M+H⁺[m/e] 299.27;-   5-(2-hydroxy-4-fluorophenyl)-1-(4-cyanophenyl)-1H-pyrazole,    retention time [min] 1.758, M+H⁺[m/e] 280.27;-   5-(2-hydroxy-4-fluorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole,    retention time [min] 1.734, M+H⁺[m/e] 285.29;-   5-(2-hydroxy-4-fluorophenyl)-1-(3-chloro-4-methylphenyl)-1H-pyrazole,    retention time [min] 2.095, M+H⁺[m/e] 303.74;-   5-(2-hydroxy-4-fluorophenyl)-1-(4-methylphenyl)-1H-pyrazole,    retention time [min] 1.865, M+H⁺[m/e] 269.29;-   5-(2-hydroxy-4-fluorophenyl)-1-(4-bromophenyl)-1H-pyrazole,    retention time [min] 2.009, M+H⁺[m/e] 334.16;-   5-(2-hydroxy-4-fluorophenyl)-1-(2-methoxyphenyl)-1H-pyrazole,    retention time [min] 1.601, M+H⁺[m/e] 285.29;-   5-(2-hydroxy-4-fluorophenyl)-1-(2-fluorophenyl)-1H-pyrazole,    retention time [min] 1.667, M+H⁺[m/e] 273.25;-   5-(2-hydroxy-4-fluorophenyl)-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.753, M+H⁺[m/e] 289.71;-   5-(2-hydroxy-4-fluorophenyl)-1-(2,6-difluorophenyl)-1H-pyrazole,    retention time [min] 1.702, M+H⁺[m/e] 291.24.

EXAMPLE 2 Preparation of5-(2,4-dihydroxyphenyl)-1-(3-nitrophenyl)-1H-pyrazole (“A2”)

124 mg of “A1” are dissolved in 3 ml of dichloromethane, and thesolution is cooled to −10°. A solution of 0.475 ml of boron tribromidein 2 ml of dichlormethane is then added dropwise, and the mixture isstirred for a further 16 hours. Conventional work-up gives 77 mg of“A2”, retention time [min] 1.418, M+H⁺[m/e] 298.27.

EXAMPLE 3

The compound 5-(2-hydroxy-4-methoxyphenyl)-1-(4-nitrophenyl)-1H-pyrazole(“A3”), retention time [min] 1.789, M+H⁺[m/e] 312.30, is obtainedanalogously to Example 1.

Reduction of the nitro group in “A3” under standard conditions intetrahydrofuran using 5% Pd/C and hydrogen and removal of the catalystand solvent gives5-(2-hydroxy-4-methoxyphenyl)-1-(4-aminophenyl)-1H-pyrazole (“A4”),retention time [min] 0.826, M+H⁺[m/e] 282.31.

An analogous procedure gives

-   5-(2-hydroxy-4-methoxyphenyl)-1-(2-nitrophenyl)-1H-pyrazole and    reduction thereof gives-   5-(2-hydroxy-4-methoxyphenyl)-1-(2-aminophenyl)-1H-pyrazole,    retention time [min] 1.123, M+H⁺[m/e] 282.31.

EXAMPLE 4

Analogously to Example 2, ether cleavage of5-(2-hydroxy-4-methoxyphenyl)-1-(4-aminophenyl)-1H-pyrazole (“A4”) givesthe compound 5-(2,4-dihydroxyphenyl)-1-(4-aminophenyl)-1H-pyrazole(“A5”), retention time [min] 0.537, M+H⁺[m/e] 268.29.

EXAMPLE 5

Analogously to Example 1, reaction of 367.5 mg of “1” with 500 mg of(2-fluorophenyl)hydrazine hydrochloride gives the compound5-(2-hydroxy-4-methoxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole (“A6”).Ether cleavage of “A6” analogously to Example 2 gives the compound5-(2,4-dihydroxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole (“A7”), retentiontime [min] 1.191, M+H⁺[m/e] 271.26.

The following compounds are obtained analogously to Example 1

-   5-(2-hydroxy-4-methoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.725, M+H⁺[m/e] 301.74;-   5-(2-hydroxy-4-methoxyphenyl)-1-(2,4-difluorophenyl)-1H-pyrazole,    retention time [min] 1.683, M+H⁺[m/e] 303.28;-   5-(2-hydroxy-4-methoxyphenyl)-1-(3,5-dichlorophenyl)-1H-pyrazole,-   5-(2-hydroxy-4-methoxyphenyl)-1-(3-chloro-2-cyanophenyl)-1H-pyrazole,-   5-(2-hydroxy-4-methoxyphenyl)-1-(2,6-dichlorophenyl)-1H-pyrazole,    retention time [min] 1.756, M+H⁺[m/e] 336.19;-   5-(2-hydroxy-4-methoxyphenyl)-1-(2-chloro-5-trifluoromethylphenyl)-1H-pyrazole,    retention time [min] 1.999, M+H⁺[m/e] 369.74;-   5-(2-hydroxy-4-methoxyphenyl)-1-(2-ethylphenyl)-1H-pyrazole,    retention time [min] 1.830, M+H⁺[m/e] 295.35;-   5-(2-hydroxy-4-methoxyphenyl)-1-(3-methoxyphenyl)-1H-pyrazole,    retention time [min] 1.680, M+H⁺[m/e] 297.33;-   5-(2-hydroxy-4-methoxyphenyl)-1-(3-cyanophenyl)-1H-pyrazole,    retention time [min] 1.650, M+H⁺[m/e] 292.31;-   5-(2-hydroxy-4-methoxyphenyl)-1-(3-trifluoromethylphenyl)-1H-pyrazole,    retention time [min] 2.002, M+H⁺[m/e] 335.30;-   5-(2-hydroxy-4-methoxyphenyl)-1-(3-chlorophenyl)-1H-pyrazole,    retention time [min] 1.852, M+H⁺[m/e] 301.74;-   5-(2-hydroxy-4-methoxyphenyl)-1-(3-carboxyphenyl)-1H-pyrazole,    retention time [min] 1.371, M+H⁺[m/e] 311.31;-   5-(2-hydroxy-4-methoxyphenyl)-1-(3-fluorophenyl)-1H-pyrazole,    retention time [min] 1.725, M+H⁺[m/e] 285.29;-   5-(2-hydroxy-4-methoxyphenyl)-1-(4-bromophenyl)-1H-pyrazole,    retention time [min] 1.921, M+H⁺[m/e] 346.20;-   5-(2-hydroxy-4-methoxyphenyl)-1-phenyl-1H-pyrazole, retention time    [min] 1.601, M+H⁺[m/e] 267.30;-   5-(2-hydroxy-4-methoxyphenyl)-1-(4-trifluoromethylphenyl)-1H-pyrazole,    retention time [min] 1.997, M+H⁺[m/e] 335.30;-   5-(2-hydroxy-4-methoxyphenyl)-1-(4-chlorophenyl)-1H-pyrazole,    retention time [min] 1.887, M+H⁺[m/e] 301.74;-   5-(2-hydroxy-4-methoxyphenyl)-1-(4-aminosulfonylphenyl)-1H-pyrazole,    retention time [min] 1.309, M+H⁺[m/e] 346.38;-   5-(2-hydroxy-4-methoxyphenyl)-1-(4-carboxyphenyl)-1H-pyrazole,    retention time [min] 1.409, M+H⁺[m/e] 311.31;-   5-(2-hydroxy-4-methoxyphenyl)-1-(4-cyanophenyl)-1H-pyrazole,    retention time [min] 1.661, M+H⁺[m/e] 292.31;-   5-(2-hydroxy-4-methoxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazole,    retention time [min] 1.600, M+H⁺[m/e] 297.33;-   5-(2-hydroxy-4-methoxyphenyl)-1-(3-chloro-4-methylphenyl)-1H-pyrazole,    retention time [min] 2.002, M+H⁺[m/e] 315.77;-   5-(2-hydroxy-4-methoxyphenyl)-1-(4-methylphenyl)-1H-pyrazole,    retention time [min] 1.726, M+H⁺[m/e] 281.33;-   5-(2-hydroxy-4-methoxyphenyl)-1-(2,6-difluorophenyl)-1H-pyrazole,    retention time [min] 1.540, M+H⁺[m/e] 303.28;-   5-(2-hydroxy-4-methoxyphenyl)-1-(4-cyano-2-nitrophenyl)-1H-pyrazole,-   5-(2-hydroxy-4-methoxyphenyl)-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole,-   5-(2-hydroxy-4-methoxyphenyl)-1-(2-nitrophenyl)-1H-pyrazole,    retention time [min] 1.509, M+H⁺[m/e] 312.30;-   5-(2-hydroxy-4-methoxyphenyl)-1-(4-ethoxycarbonylphenyl)-1H-pyrazole,    retention time [min] 1.899, M+H⁺[m/e] 339.36;-   5-(2-hydroxy-4-methoxyphenyl)-1-(2-aminophenyl)-1H-pyrazole,    and ether cleavage thereof gives the following compounds-   5-(2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole, retention    time [min] 1.548, M+H⁺[m/e] 287.72;-   5-(2,4-dihydroxyphenyl)-1-(2,4-difluorophenyl)-1H-pyrazole,    retention time [min] 1.288, M+H⁺[m/e] 289.25;-   5-(2,4-dihydroxyphenyl)-1-(3,5-dichlorophenyl)-1H-pyrazole,    retention time [min] 1.807, M+H⁺[m/e] 322.16;-   5-(2,4-dihydroxyphenyl)-1-(3-chloro-2-cyanophenyl)-1H-pyrazole,    retention time [min] 1.726, M+H⁺[m/e] 312.73;-   5-(2,4-dihydroxyphenyl)-1-(2,6-dichlorophenyl)-1H-pyrazole,    retention time [min] 1.356, M+H⁺[m/e] 322.16;-   5-(2,4-dihydroxyphenyl)-1-(2-chloro-5-trifluoromethylphenyl)-1H-pyrazole,    retention time [min] 1.641, M+H⁺[m/e] 355.71;-   5-(2,4-dihydroxyphenyl)-1-(2-ethylphenyl)-1H-pyrazole, retention    time [min] 1.439, M+H⁺[m/e] 281.33;-   5-(2,4-dihydroxyphenyl)-1-(3-hydroxyphenyl)-1H-pyrazole, retention    time [min] 0.984, M+H⁺[m/e] 269.27;-   5-(2,4-dihydroxyphenyl)-1-(3-cyanophenyl)-1H-pyrazole, retention    time [min] 1.296, M+H⁺[m/e] 278.28;-   5-(2,4-dihydroxyphenyl)-1-(3-trifluoromethylphenyl)-1H-pyrazole,    retention time [min] 1.665, M+H⁺[m/e] 321.27;-   5-(2,4-dihydroxyphenyl)-1-(3-chlorophenyl)-1H-pyrazole, retention    time [min] 1.506, M+H⁺[m/e] 287.72;-   5-(2,4-dihydroxyphenyl)-1-(3-carboxyphenyl)-1H-pyrazole,-   5-(2,4-dihydroxyphenyl)-1-(3-fluorophenyl)-1H-pyrazole, retention    time [min] 1.360, M+H⁺[m/e] 271.26;-   5-(2,4-dihydroxyphenyl)-1-(4-bromophenyl)-1H-pyrazole, retention    time [min] 1.545, M+H⁺[m/e] 332.17;-   5-(2,4-dihydroxyphenyl)-1-phenyl-1H-pyrazole, retention time [min]    1.217, M+H⁺[m/e] 253.27;-   5-(2,4-dihydroxyphenyl)-1-(4-trifluoromethylphenyl)-1H-pyrazole,    retention time [min] 1.687, M+H⁺[m/e] 321.27;-   5-(2,4-dihydroxyphenyl)-1-(4-chlorophenyl)-1H-pyrazole, retention    time [min] 1.506, M+H⁺[m/e] 287.72;-   5-(2,4-dihydroxyphenyl)-1-(4-aminosulfonylphenyl)-1H-pyrazole,    retention time [min] 0.936, M+H⁺[m/e] 332.35;-   5-(2,4-dihydroxyphenyl)-1-(4-carboxyphenyl)-1H-pyrazole, retention    time [min] 1.051, M+H⁺[m/e] 297.28;-   5-(2,4-dihydroxyphenyl)-1-(4-cyanophenyl)-1H-pyrazole, retention    time [min] 1.325, M+H⁺[m/e] 278.28;-   5-(2,4-dihydroxyphenyl)-1-(4-hydroxyphenyl)-1H-pyrazole, retention    time [min] 0.907, M+H⁺[m/e] 269.27;-   5-(2,4-dihydroxyphenyl)-1-(3-chloro-4-methylphenyl)-1H-pyrazole,    retention time [min] 1.638, M+H⁺[m/e] 301.74;-   5-(2,4-dihydroxyphenyl)-1-(4-methylphenyl)-1H-pyrazole, retention    time [min] 1.384, M+H⁺[m/e] 267.30;-   5-(2,4-dihydroxyphenyl)-1-(2,6-difluorophenyl)-1H-pyrazole,    retention time [min] 1.175, M+H⁺[m/e] 289.25;-   5-(2,4-dihydroxyphenyl)-1-(4-cyano-2-nitrophenyl)-1H-pyrazole,-   5-(2,4-dihydroxyphenyl)-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole,-   5-(2,4-dihydroxyphenyl)-1-(2-nitrophenyl)-1H-pyrazole,-   5-(2,4-dihydroxyphenyl)-1-(4-ethoxycarbonylphenyl)-1H-pyrazole,-   5-(2,4-dihydroxyphenyl)-1-(2-aminophenyl)-1H-pyrazole, retention    time [min] 0.903, M+H⁺[m/e] 268.29;-   5-(2,4-dihydroxyphenyl)-1-(2-methylphenyl)-1H-pyrazole, retention    time [min] 1.498, M+H⁺[m/e] 267.30;-   5-(2,4-dihydroxy-5-bromophenyl)-1-(2-aminophenyl)-1H-pyrazole,    retention time [min] 1.478, M+H⁺[m/e] 347.19;-   5-(2,4-dihydroxyphenyl)-1-(3-aminophenyl)-1H-pyrazole, retention    time [min] 0.806, M+H⁺[m/e] 268.29;-   5-(2,4-dihydroxy-5-bromophenyl)-1-(3-aminophenyl)-1H-pyrazole,    M+H⁺[m/e] 347.19;-   5-(2,4-dihydroxyphenyl)-1-(3-methylphenyl)-1H-pyrazole, retention    time [min] 1.547, M+H⁺[m/e] 267.30;-   5-(2,4-dihydroxyphenyl)-1-(2-carboxyphenyl)-1H-pyrazole, retention    time [min] 0.95, M+H⁺[m/e] 297.28;-   5-(2,4-dihydroxyphenyl)-1-(4-fluorophenyl)-1H-pyrazole, retention    time [min] 1.437, M+H⁺[m/e] 271.26;-   5-(2,4-dihydroxy-5-bromophenyl)-1-(4-fluorophenyl)-1H-pyrazole,    retention time [min] 1.809, M+H⁺[m/e] 350.16;-   5-(2,4-dihydroxy-5-bromophenyl)-1-(3-methylphenyl)-1H-pyrazole,    M+H⁺[m/e] 346.20.

The following compounds are obtained analogously

-   5-(2,4-dihydroxy-5-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.599, M+H⁺[m/e] 366.62;-   5-(2,4-dihydroxy-5-chlorophenyl)-1-(2-fluorophenyl)-1H-pyrazole,    retention time [min] 1.511, M+H⁺[m/e] 305.71;-   5-(2,4-dihydroxy-5-bromophenyl)-1-(2-ethylphenyl)-1H-pyrazole,    retention time [min] 1.659, M+H⁺[m/e] 360.23.

EXAMPLE 6 1. N,N-dimethylformamide dimethyl acetal (DMA) is added to asolution of 2,4-dimethoxyacetophenone in dimethylformamide (DMF), andthe mixture is refluxed for 24 hours on a water separator.

Removal of the solvent and conventional work-up gives (“1a”)

2. A solution of 7.0 g of “1a” and 4.68 g of (4-nitrophenyl)hydrazine in100 ml of ethanol is refluxed for 16 hours. Removal of the solvent andconventional work-up gives 6.6 g of5-(2,4-dimethoxyphenyl)-1-(4-nitrophenyl)-1H-pyrazole (“A8”).

3. Analogously to Example 3, reduction thereof using hydrogen on Pd/Cgives the compound 5-(2,4-dimethoxyphenyl)-1-(4-aminophenyl)-1H-pyrazole(“A9”). 4. Reaction of “A9” with the following acid chlorides

-   -   benzoyl chloride,    -   acetyl chloride,    -   propionyl chloride,    -   butyryl chloride,    -   pyridine-4-carbonyl chloride,    -   phenylacetyl chloride        under standard acylation conditions gives the following N-acyl        compounds

-   5-(2,4-dimethoxyphenyl)-1-(4-benzoylaminophenyl)-1H-pyrazole,

-   5-(2,4-dimethoxyphenyl)-1-(4-acetylaminophenyl)-1H-pyrazole,

-   5-(2,4-dimethoxyphenyl)-1-(4-propionylaminophenyl)-1H-pyrazole,

-   5-(2,4-dimethoxyphenyl)-1-[4-(butyrylamino)phenyl]1H-pyrazole,

-   5-(2,4-dimethoxyphenyl)-1-[4-(pyridin-4-ylcarbonylamino)phenyl]1H-pyrazole,

-   5-(2,4-dimethoxyphenyl)-1-[4-(phenylacetylamino)phenyl]1H-pyrazole.

5. Ether cleavage thereof analogously to Example 2 gives the followingcompounds

-   5-(2,4-dihydroxyphenyl)-1-(4-benzoylaminophenyl)-1H-pyrazole,    retention time [min] 1.734, M+H⁺[m/e] 372.40;-   5-(2,4-dihydroxyphenyl)-1-(4-acetylaminophenyl)-1H-pyrazole,-   5-(2,4-dihydroxyphenyl)-1-(4-propionylaminophenyl)-1H-pyrazole,-   5-(2,4-dihydroxyphenyl)-1-[4-(butyrylamino)phenyl]1H-pyrazole,-   5-(2,4-dihydroxyphenyl)-1-[4-(pyridin-4-ylcarbonylamino)phenyl]1H-pyrazole,    retention time [min] 1.012, M+H⁺[m/e] 373.38;-   5-(2,4-dihydroxyphenyl)-1-[4-(phenylacetylamino)phenyl]1H-pyrazole,    retention time [min] 1.495, M+H⁺[m/e] 386.42

The following are obtained analogously

-   5-(2,4-dihydroxyphenyl)-1-(3-benzoylaminophenyl)-1H-pyrazole,    retention time [min] 1.427, M+H⁺[m/e] 372.40;-   5-(2,4-dihydroxyphenyl)-1-[4-(pyridin-3-ylcarbonylamino)phenyl]1H-pyrazole,    retention time [min] 1.214, M+H⁺[m/e] 373.38;-   5-(2,4-dihydroxyphenyl)-1-[3-(pyridin-2-ylcarbonylamino)phenyl]1H-pyrazole,    retention time [min] 1.683, M+H⁺[m/e] 373.38;-   5-(2,4-dihydroxyphenyl)-1-[4-(pyridin-2-ylcarbonylamino)phenyl]1H-pyrazole,    retention time [min] 1.669, M+H⁺[m/e] 373.38;-   5-(2,4-dihydroxyphenyl)-1-[3-(pyridin-3-ylcarbonylamino)phenyl]1H-pyrazole,    retention time [min] 1.205, M+H⁺[m/e] 373.38;-   5-(2,4-dihydroxyphenyl)-1-[3-(pyridin-4-ylcarbonylamino)phenyl]1H-pyrazole,    retention time [min] 1.210, M+H⁺[m/e] 373.38;-   5-(2,4-dihydroxyphenyl)-1-[4-(methoxyethylcarbonylamino)phenyl]-1H-pyrazole,    M+H⁺[m/e] 354.38;-   5-(2,4-dihydroxyphenyl)-1-[2-(pyridin-3-ylcarbonylamino)phenyl]1H-pyrazole,    retention time [min] 1.159, M+H⁺[m/e] 373.38;-   5-(2,4-dihydroxyphenyl)-1-(2-benzoylaminophenyl)-1H-pyrazole,    retention time [min] 1.875, M+H⁺[m/e] 372.40;-   5-(2,4-dihydroxy-5-bromophenyl)-1-(2-benzoylaminophenyl)-1H-pyrazole,    retention time [min] 2.120, M+H⁺[m/e] 451.30;-   5-(2,4-dihydroxyphenyl)-1-[2-(benzylcarbonylamino)phenyl]1H-pyrazole,    retention time [min] 1.820, M+H⁺[m/e] 386.42;-   5-(2,4-dihydroxy-5-bromophenyl)-1-[2-(benzylcarbonylamino)phenyl]-1H-pyrazole,    retention time [min] 2.079, M+H⁺[m/e] 465.32;-   5-(2,4-dihydroxyphenyl)-1-[2-(pyridin-4-ylcarbonylamino)phenyl]1H-pyrazole,    retention time [min] 1.148, M+H⁺[m/e] 373.38.

EXAMPLE 7

Instead of the methyl groups in “1a”, a benzyl group may alsoadvantageously be employed as hydroxyl-protecting group.

Alternatively, acetyl or p-methoxybenzyl can be used.

1. N,N-dimethylformamide dimethyl acetal (DMA) is added to a solution of2,4-dibenzyloxyacetophenone in dimethylformamide (DMF), and the mixtureis refluxed for 24 hours on a water separator. Removal of the solventand conventional work-up gives (“1b”)

2. A solution of “1b” and (4-carboxyphenyl)hydrazine in ethanol isrefluxed for 16 hours. Removal of the solvent and conventional work-upgives 5-(2,4-dibenzyloxyphenyl)-1-(4-carboxyphenyl)-1H-pyrazole (“A10”).

Reaction thereof with thionyl chloride under standard conditions gives5-(2,4-dibenzyloxyphenyl)-1-(4-chlorocarbonylphenyl)-1H-pyrazole(“A11”).

Reaction of “A11” with the following amines

-   -   benzylamine,    -   methylamine,    -   ethylamine,    -   propylamine,        under standard acylation conditions gives the following N-acyl        compounds

-   5-(2,4-dibenzyloxyphenyl)-1-[4-(benzylaminocarbonyl)phenyl]1H-pyrazole,

-   5-(2,4-dibenzyloxyphenyl)-1-[4-(methylaminocarbonyl)phenyl]1H-pyrazole,

-   5-(2,4-dibenzyloxyphenyl)-1-[4-(ethylaminocarbonyl)phenyl]1H-pyrazole,

-   5-(2,4-dibenzyloxyphenyl)-1-[4-(propylaminocarbonyl)phenyl]1H-pyrazole.

The ether cleavage is carried out using hydrogen on Pd/C analogously toExample 3. The following compounds are obtained

-   5-(2,4-dihydroxyphenyl)-1-[4-(benzylaminocarbonyl)phenyl]1H-pyrazole,-   5-(2,4-dihydroxyphenyl)-1-[4-(methylaminocarbonyl)phenyl]1H-pyrazole,-   5-(2,4-dihydroxyphenyl)-1-[4-(ethylaminocarbonyl)phenyl]1H-pyrazole,-   5-(2,4-dihydroxyphenyl)-1-[4-(propylaminocarbonyl)phenyl]1H-pyrazole.

EXAMPLE 8

Synthetic scheme for the preparation of sulfonamide derivatives

Preparation of5-(5-aminosulfonyl-2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole(“C3”)

8.1 18.0 g of 5-(2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole(“B1”; obtainable analogously to Example 1) are added at −5° to 30 ml ofchlorosulfonic acid, and the mixture is stirred at room temperature fora further 3 hours. The mixture is poured onto ice, the precipitatedcrystals are separated off and washed with water, giving 23.6 g of5-(5-chlorosulfonyl-2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole(“B2”).

8.2 20 ml of a 32% ammonia solution are added at room temperature to asolution of 413.3 mg of “B2” in 5 ml of dry methanol. The mixture isstirred overnight, approximately half of the solvent is removed, theprecipitated crystals are separated off and washed with water, giving230 mg of5-(5-aminosulfonyl-2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole(“C1”) and, as by-product,5-(5-hydroxysulfonyl-2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole(“C2”).

8.3 450 mg of “C1” are dissolved in 5 ml of dichloromethane under anitrogen atmosphere, and the solution is cooled to −20° in a dry-icebath. 1 ml of boron tribromide is then slowly added dropwise using asyringe via a septum, and the mixture is stirred at room temperature fora further 16 hours.

The mixture is cooled to −20°, and methanol and finally one drop ofwater are added dropwise. The solvent is removed at room temperature,and the residue is dissolved in 2 ml of methanol.

Separation via a 130 g RP-18 column by means of a CombiFlash COMPANIONinstrument gives 122 mg of “C3”, retention time [min] 0.837, M+H⁺[m/e]366.79.

Analogous reaction of “B2” with

-   -   N-ethyl-N′-methylamine,    -   N,N′-diethylamine,    -   piperidine,    -   aniline,    -   2-fluoroaniline,    -   3-fluoroaniline,    -   4-fluoroaniline,    -   3-aminopyridine,    -   3-hydroxymethylpiperidine,    -   N-benzyl-N′-methylamine,    -   N,N′-dimethylamine,    -   N-(2-hydroxyethyl)-N′-methylamine,    -   N-cyclohexyl-N′-methylamine,    -   3-methylamino-1,2-propanediol,    -   N-butyl-N′-methylamine,    -   N-propyl-N′-methylamine,    -   N-(2-cyanoethyl)-N′-methylamine,    -   N-isopropyl-N′-methylamine,    -   N,N′-dimethyl-2-methylaminoacetamide        (sarcosine-N,N′-dimethylamide),    -   2-hydroxymethylpiperidine,    -   morpholine,    -   2-(N,N′-diethylaminomethyl)piperidine,    -   1-methylpiperazine,    -   30 methylamine,    -   4-aminopyridine        gives the compounds

-   5-[5-(N-ethyl-N′-methylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N,N′-diethylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(piperidine-1-sulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-phenylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-{5-[N-(2-fluorophenyl)aminosulfonyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,

-   5-{5-[N-(3-fluorophenyl)aminosulfonyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,

-   5-{5-[N-(4-fluorophenyl)aminosulfonyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,

-   5-{5-[N-(pyridin-3-yl)aminosulfonyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(3-hydroxymethylpiperidine-1-sulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-benzyl-N-methylaminosulfonyl)-2,4-dimethoxyphenyl]—(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N,N′-dimethylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-(2-hydroxyethyl)-N′-methylaminosulfonyl)-2,4-dimethoxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-cyclohexyl-N′-methylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-(2,3-dihydroxypropyl)-N′-methylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-butyl-N′-methylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-(2-cyanoethyl)-N′-methylaminosulfonyl)-2,4-dimethoxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-isopropyl-N′-methylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-{5-[N-(dimethylaminocarbonylmethyl)-N′-methylaminosulfonyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(2-hydroxymethylpiperidine-1-sulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(morpholine-4-sulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-{5-[2-(N,N′-diethylaminomethyl)piperidin-4-yl]sulfonyl}2,4-dimethoxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(1-methylpiperazin-4-yl)sulfonyl]2,4-dimethoxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-methylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-{5-[N-(pyridin-4-yl)aminosulfonyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,    and ether cleavage thereof gives the compounds

-   5-[5-(N-ethyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.367, M+H⁺[m/e] 408.88;

-   5-[5-(N—N′-diethylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.468, M+H⁺[m/e] 422.90;

-   5-[5-(piperidine-1-sulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.558, M+H⁺[m/e] 434.91;

-   5-[5-(N-phenylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.620, M+H⁺[m/e] 442.89 and

-   5-[5-(N-phenylaminosulfonyl)-2-hydroxy-4-methoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    M+H⁺[m/e] 456.92;

-   5-{5-[N-(2-fluorophenyl)aminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.475, M+H⁺[m/e] 460.88;

-   5-{5-[N-(3-fluorophenyl)aminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.502, M+H⁺[m/e] 460.88;

-   5-{5-[N-(4-fluorophenyl)aminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.478, M+H⁺[m/e] 460.88;

-   5-{5-[N-(pyridin-3-yl)aminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 0.923, M+H⁺[m/e] 443.99;

-   5-[5-(3-hydroxymethylpiperidine-1-sulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.176, M+H⁺[m/e] 464.94 and

-   5-[5-(3-bromomethylpiperidine-1-sulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    M+H⁺[m/e] 527.84;

-   5-[5-(N-benzyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.710, M+H⁺[m/e] 470.95 and

-   5-[5-(N-benzyl-N′-methylaminosulfonyl)-2-methoxy-4-hydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N—N′-dimethylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.234, M+H⁺[m/e] 394.85;

-   5-[5-(N-(2-bromoethyl)-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.483, M+H⁺[m/e] 487.78;

-   5-[5-(N-cyclohexyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.738, M+H⁺[m/e] 462.97;

-   5-[5-(N-(2,3-dibromopropyl)-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.694, M+H⁺[m/e] 580.70;

-   5-[5-(N-butyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.665, M+H⁺[m/e] 436.93;

-   5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.511, M+H⁺[m/e] 422.90;

-   5-{5-[N-(2-cyanoethyl)-N′-methylaminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.271, M+H⁺[m/e] 433.89;

-   5-[5-(N-isopropyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.412, M+H⁺[m/e] 422.90;

-   5-{5-[N-(dimethylaminocarbonylmethyl)-N′-methylaminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.044, M+H⁺[m/e] 465.93;

-   5-[5-(2-hydroxymethylpiperidine-1-sulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.159, M+H⁺[m/e] 464.94;

-   5-[5-(morpholine-4-sulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole    and

-   5-{5-[N-(2-hydroxyethyl)-N′-(2-bromoethyl)aminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.250, M+H⁺[m/e] 517.80 and

-   5-{5-[N-(2-hydroxyethyl)-N′-(2-bromoethyl)aminosulfonyl]2-hydroxy-4-methoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole;

-   5-{5-[2-(N,N′-diethylaminomethyl)piperidin-4-yl]sulfonyl}2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 0.967, M+H⁺[m/e] 520.06;

-   5-[5-(1-methylpiperazin-4-yl)sulfonyl]2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 0.848, M+H⁺[m/e] 449.93;

-   5-[5-(N-methylaminosulfonyl)-2,4-hydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.011, M+H⁺[m/e] 380.82;

-   5-{5-[N-(pyridin-4-yl)aminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 0.784, M+H⁺[m/e] 443.88.

The compounds

-   5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,    retention time [min] 1.441, M+H⁺[m/e] 402.48;-   5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,    retention time [min] 1.395, M+H⁺[m/e] 406.45, are obtained    analogously

EXAMPLE 9

Analogously to Example 8, reaction of5-(5-chlorosulfonyl-2,4-dimethoxyphenyl)-1-(2-methylphenyl)-1H-pyrazole(“D1”) with

-   -   aniline,    -   benzylamine,    -   N,N′-diethylamine,    -   ethylamine,    -   ammonia,        gives the compounds

-   5-[5-(N-phenylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,

-   5-[5-(N-benzylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,

-   5-[5-(N,N′-diethylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,

-   5-[5-(ethylaminosulfonyl)-2,4-dimethoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,

-   5-[5-(aminosulfonyl)-2,4-dimethoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,    and ether cleavage thereof gives the compounds

-   5-[5-(N-phenylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,    retention time [min] 1.438, M+H⁺[m/e] 422.47 and

-   5-[5-(N-phenylaminosulfonyl)-2-hydroxy-4-methoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,    retention time [min] 1.662, M+H⁺[m/e] 436.50;

-   5-[5-(N-benzylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,    retention time [min] 1.483, M+H⁺[m/e] 436.50 and

-   5-[5-(N-benzylaminosulfonyl)-2-hydroxy-4-methoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,    retention time [min] 1.702, M+H⁺[m/e] 436.50;

-   5-[5-(N,N′-diethylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,    retention time [min] 1.497, M+H⁺[m/e] 402.48 and

-   5-[5-(N,N′-diethylaminosulfonyl)-2-hydroxy-4-methoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,    retention time [min] 1.790, M+H⁺[m/e] 416.51;

-   5-[5-(ethylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,    retention time [min] 1.423, M+H⁺[m/e] 374.43 and

-   5-[5-(ethylaminosulfonyl)-2-hydroxy-4-methoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,    retention time [min] 1.156, M+H⁺[m/e] 388.46;

-   5-[5-(aminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,    retention time [min] 1.573, M+H⁺[m/e] 346.38 and

-   5-[5-(aminosulfonyl)-2-hydroxy-4-methoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,    retention time [min] 1.864, M+H⁺[m/e] 360.40.

EXAMPLE 10

General scheme for the preparation of iodine compounds of the formula I

Preparation of5-[5-iodo-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole:

10.1 63.45 g of iodine and subsequently 88.57 g of Selectfluor are addedat room temperature to a solution of 90.1 g of 2,4-dimethoxyacetophenonein 2.5 l of acetonitrile, and the mixture is stirred for a further 2.5hours. Conventional work-up and crystallisation from 400 ml of methanolgives 166 g of 2,4-dimethoxy-5-iodoacetophenone (“E1”).

10.2 A mixture of 18.3 g of “E1” and 50 ml of N,N-dimethylformamidedimethyl acetal is refluxed (1700) for 16 hours on a water separator.The solvent is separated off, 100 ml of MTB ether are added, and thecrystals are separated off, giving 15.5 g of(E)-3-dimethylamino-1-(5-iodo-2,4-dimethoxyphenyl)propenone (“E2”).

10.3 A solution of 8.05 g of “E2” and 4.0 g of (2-chlorophenyl)hydrazinehydrochloride in 50 ml of ethanol is refluxed for 16 hours. The reactionmixture is purified by chromatography (ISCO/330 g column; petroleumether/ethyl acetate: 10/90 to 1/1), giving 8.4 g of5-[5-iodo-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole (“E2a”).

Ether cleavage thereof using boron tribromide gives5-[5-iodo-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole.

Analogous reaction of “E2” with

-   -   (2-fluorophenyl)hydrazine        gives the compound

-   5-[5-iodo-2,4-dimethoxyphenyl]1-(2-fluorophenyl)-1H-pyrazole (“E3a”)    and ether cleavage thereof gives

-   5-[5-iodo-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole (“E3”),    M+H⁺[m/e] 397.16.

EXAMPLE 11

General scheme for the preparation of compounds of the formula I bymeans of Heck reaction

11-A

Preparation of5-[5-carboxyethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole and5-[5-methoxycarbonylethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole:

11.A.1 A mixture of 1.061 g of “E3a”, 250.29 mg of ethyl acrylate, 0.7ml of triethylamine, 22.45 mg of palladium(II) acetate (47% of Pd),30.74 mg of tri-o-tolylphosphine and 5 ml of acetonitrile is irradiatedin the microwave for 30 minutes at 160°. Toluene is added to thereaction mixture, which is extracted a number of times with water. Theorganic phase is dried and evaporated. The product is purified bychromatography (ISCO/40 g column; petroleum ether/ethyl acetate: 4/1 to1/1), giving 0.7 g of ethyl3-{5-[2-(2-fluorophenyl)-2H-pyrazol-3-yl]2,4-dimethoxyphenyl}acrylate(“E4”) as isomer mixture (E/Z) in the ratio 95/5;

11.A.2 A mixture of 383 mg of “E4”, 400 mg of 5% Pd/C (56% of water) and10 ml of THF is hydrogenated for 16 hours at 1.4 bar and roomtemperature in a BÜCHI apparatus. Removal of the catalyst and removal ofthe solvent gives 398.4 mg of5-[5-(2-ethoxycarbonylethyl)-2,4-dimethoxyphenyl]-1-(2-fluorophenyl)-1H-pyrazole(“E5”).

11.A.3 Ether cleavage analogously to Example 8.3 gives a mixture of 73mg of5-[5-(2-carboxyethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,M+H⁺[m/e] 343.33 and 356 mg of5-[5-(2-methoxycarbonylethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,M+H⁺[m/e] 357.35.

11.B

11.B.1 Analogously to Example 11.A.1, reaction of “E2a” with styrenegives the compound5-[5-styryl-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole (“E6”)

11.B.2 Hydrogenation of “E6” gives the compound5-[5-(2-phenylethyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazoleand ether cleavage thereof gives the compound5-[5-(2-phenylethyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,retention time [min] 1.872, M+H⁺[m/e] 391.87.

An analogous reaction gives the compounds

5-[5-styryl-2,4-dimethoxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,hydrogenation thereof gives5-[5-(2-phenylethyl)-2,4-dimethoxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,and ether cleavage thereof gives5-[5-(2-phenylethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,M+H⁺[m/e] 375.41.

The compound5-[5-(2-phenyl-2-methoxyethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,M+H⁺[m/e] 405.44, is formed as by-product during the ether cleavage.

Ether cleavage of5-[5-styryl-2,4-dimethoxyphenyl]1-(2-fluorophenyl)-1H-pyrazole gives5-[5-styryl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,M+H⁺[m/e] 373.40.

11.C

11.C.1 Analogously to Example 1.A.1, reaction of “E2a” with4-vinylpyridine gives the compound5-{5-[2-(pyridin-4-yl)vinyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole(“E7”).

11.C.2 Hydrogenation of “E7” using 5% Pt/C as catalyst gives thecompound5-{5-[2-(pyridin-4-yl)ethyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazoleand ether cleavage thereof gives the compound5-{5-[2-(pyridin-4-yl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,retention time [min] 1.397, M+H⁺[m/e] 392.86.

Ether cleavage of “E7” gives the compound5-{5-[2-(pyridin-4-yl)vinyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole.

11.D

Analogous reaction of “E2a” with 2-vinylpyridine gives the compound5-{5-[2-(pyridin-2-yl)vinyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole(“E8”).

Hydrogenation and subsequent ether cleavage thereof gives the compound5-{5-[2-(pyridin-2-yl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,retention time [min] 0.702, M+H⁺[m/e] 392.86.

11.E

Analogous reaction of “E2a” with 4-fluorostyrene gives the compounds5-[5-(4-fluorostyryl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole(“E9”) and5-{5-[1-(4-fluorophenyl)vinyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole.

Hydrogenation and subsequent ether cleavage of “E9” gives the compound5-{5-[2-(4-fluorophenyl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,retention time [min] 1.882, M+H⁺[m/e] 409.86.

11.F

Analogous reaction of “E2a” with 3-fluorostyrene gives the compounds5-[5-(3-fluorostyryl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole(“E10”) and5-{5-[1-(3-fluorophenyl)vinyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole.

Hydrogenation and subsequent ether cleavage of “E10” gives the compound5-{5-[2-(3-fluorophenyl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,retention time [min] 1.895, M+H⁺[m/e] 409.86.

11.G

Analogous reaction of “E2a” with 2-fluorostyrene gives the compounds5-[5-(2-fluorostyryl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole(“E111”) and5-{5-[1-(2-fluorophenyl)vinyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole.

Hydrogenation and subsequent ether cleavage of “E11” gives the compound5-{5-[2-(2-fluorophenyl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,retention time [min] 1.866, M+H⁺[m/e] 409.86.

11.H

Hydrogenation of 700 mg of “E9” in THF with addition of 1.8 g of 5% Pt/Calso gives, after 30 hours, complete dechlorination in addition tohydrogenation of the double bond. Removal of the catalyst and removal ofthe solvent gives 470 mg of5-{5-[1-(4-fluorophenyl)ethyl]2,4-dimethoxyphenyl}-1-phenyl-1H-pyrazole.

Ether cleavage thereof gives5-{5-[1-(4-fluorophenyl)ethyl]2,4-dihydroxyphenyl}-1-phenyl-1H-pyrazole,retention time [min] 1.874, M+H⁺[m/e] 375.41.

11.I

Analogous reaction of “E2a” with 3-nitrostyrene gives the compounds5-[5-(3-nitrostyryl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole(“E12”).

Hydrogenation of “E12” gives the compound5-{5-[2-(3-aminophenyl)ethyl]-2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole(“E13”).

Acylation of “E13” using trifluoroacetyl chloride and subsequent ethercleavage gives the compound5-{5-[2-(3-trifluoroacetamidophenyl)ethyl]-2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole.

Reaction of “E13” with BOC-glycine and subsequent removal of the BOCgroup and also of the methyl ether gives

11.J

Analogous reaction of “E2a” with 3-carboxystyrene gives the compound5-[5-(3-carboxystyryl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazoleand hydrogenation thereof gives5-{5-[2-(3-carboxyphenyl)ethyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole.Ether cleavage gives5-{5-[2-(3-carboxyphenyl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole.

EXAMPLE 12

12.1 The compound5-[5-iodo-2,4-dimethoxyphenyl]1-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1H-pyrazoleis obtained analogously to Example 10

Analogously to Example 11, reaction thereof with1-chloro-2-vinylbenzene, hydrogenation and subsequent ether cleavagegives the compound5-{5-[2-(2-chlorophenyl)ethyl]2,4-dihydroxyphenyl}-1-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1H-pyrazole

12.2 Analogous reaction of “E2a” with propene, hydrogenation and ethercleavage gives the compound5-{5-propyl-2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole

12.3 Analogous reaction of “E2a” with methylenecyclopropane,hydrogenation and ether cleavage gives the compound5-{5-cyclopropylmethyl-2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole.

12.4 Analogous reaction of5-[5-iodo-2,4-dimethoxyphenyl]1-(3-methylphenyl)-1H-pyrazole with2-methyl-1-butene, hydrogenation and ether cleavage gives the compound5-{5-(2-methylbutyl)-2,4-dihydroxyphenyl}-1-(3-methylphenyl)-1H-pyrazole.

12.5 Analogous reaction of “E2a” with 2-fluoropropene, hydrogenation andether cleavage gives the compound5-{5-(2-fluoropropyl)-2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole.

12.6 Analogous reaction of5-[5-iodo-2,4-dimethoxyphenyl]1-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1H-pyrazolewith 4-vinyltoluene, hydrogenation and ether cleavage gives the compound5-{5-[2-(4-methylphenyl)ethyl]2,4-dihydroxyphenyl}-1-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1H-pyrazole.

12.7 Analogous reaction of “E2a” with isopropenylbenzene, hydrogenationand ether cleavage gives the compound5-{5-(2-phenylpropyl)-2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole.

12.8 Analogous reaction of5-[5-iodo-2,4-dimethoxyphenyl]1-(2-nitrophenyl)-1H-pyrazole withisopropenylbenzene, hydrogenation and ether cleavage gives the compound5-{5-(2-phenylpropyl)-2,4-dihydroxyphenyl}-1-(2-aminophenyl)-1H-pyrazole.

EXAMPLE 13

General reaction scheme for the preparation of compounds of the formulaI in which

R² denotes —(CH₂)_(r)—X—(CH)_(s)—R, R denotes Ar or Het, X denotes NH,NA or O,

r denotes 1,s denotes 0 or 1:

13.A

13.A.1 A solution of 1 g of “E2a” in 10 ml of THF is cooled to −70°. 1.6ml of butyllithium (15% solution in n-hexane) are added dropwise, duringwhich the temperature is held between −70 and 600. The mixture isstirred for a further 30 minutes. 0.25 ml of N-formylpiperidine is thenadded dropwise, and the mixture is allowed to warm to −15°.Semi-concentrated hydrochloric acid is added dropwise, and the mixtureis extracted with MTB ether. The organic phases are dried. Removal ofthe solvent gives5-[5-formyl-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole (“E2b”).

13.A.2 Ether cleavage of “E2b” using BBr₃ gives the compound5-[5-formyl-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole (“E2c”).

13.A.3 Reaction of “E2c” with aniline (formation of the Schiff base)gives the compound

13.A.4 Reduction of the double bond under standard conditions gives5-[5-phenylaminomethyl-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole.

The compound5-[5-phenylaminomethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazoleis obtained analogously.

13.B

13.B.1 Etherification of “E2c” using tert-butyldimethylsilyl chlorideunder standard conditions gives5-[5-formyl-2,4-di-(tert-butyldimethylsilyoxy)phenyl]-1-(2-chlorophenyl)-1H-pyrazole(“E2d”).

13.B.2 Reduction of the formyl group in “E2d” using NaBH₄ under standardconditions gives5-[5-hydroxymethyl-2,4-di-(tert-butyldimethylsilyoxy)phenyl]-1-(2-chlorophenyl)-1H-pyrazole(“E2e”).

13.B.3 Reaction of “E2e”, phenol, triphenylphosphine and diethylazodicarboxylate (“DEAD”)

in a Mitsunobu reaction gives the compound5-[5-phenoxymethyl-2,4-di-(tert-butyldimethylsilyoxy)phenyl]-1-(2-chlorophenyl)-1H-pyrazole.Ether cleavage thereof using HCl in dioxane gives5-[5-phenoxymethyl-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole.

The compound5-[5-phenoxymethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole isobtained analogously.

13.C

13.C.1 Analogously to 13.B.3, reaction of “E2e” with thiophenol, PPh₃and DEAD gives the compound5-[5-phenylthiomethyl-2,4-di-(tert-butyldimethylsilyoxy)phenyl]-1-(2-chlorophenyl)-1H-pyrazoleand ether cleavage thereof gives5-[5-phenylthiomethyl-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole.

The compounds

-   5-[5-phenylthiomethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,-   5-[5-(4-methoxyphenylthiomethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,    are obtained analogously.

Simple oxidation of5-[5-phenylthiomethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazoleand

-   5-[5-(4-methoxyphenylthiomethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole    gives-   5-[5-phenylsulfinylmethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole    and-   5-[5-(4-methoxyphenylsulfinylmethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole.

Oxidation of5-[5-phenylthiomethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazoleand

-   5-[5-(4-methoxyphenylthiomethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole    using sodium perborate in acetic acid under standard conditions    gives the compounds-   5-[5-phenylsulfonylmethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole    and-   5-[5-(4-methoxyphenylsulfonylmethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole.

EXAMPLE 14 14.A

14.A.1 A mixture of 440.6 mg of “E2a”, 153 μl of thiophenol, 194.3 mg ofcopper(I) iodide, 139.6 mg of N,N-dimethylglycine hydrochloride, 651.6mg of caesium carbonate and 4 ml of 1,4-dioxane is stirred at 90° for 50hours. Conventional work-up gives 510 mg of5-[5-phenylsulfanyl-2,4-dimethoxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole(“F1”).

14.A.2 Reaction of “F1.” with BBr₃ in dichloromethane gives a mixture of5-[5-phenylsulfanyl-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,retention time [min] 1.767, M+H⁺[m/e] 395.88 and

-   5-[5-phenylsulfanyl-2-hydroxy-4-methoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 2.021, M+H⁺[m/e] 409.91.

14.A.3 Oxidation of5-[5-phenylsulfanyl-2-hydroxy-4-methoxyphenyl]1-(2-chlorophenyl)-1H-pyrazoleusing sodium perborate in glacial acetic acid gives5-[5-phenylsulfonyl-2-hydroxy-4-methoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,and ether cleavage thereof gives5-[5-phenylsulfonyl-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,retention time [min] 1.403, M+H⁺[m/e] 427.88.

14.B

14.B.1 Analogously to 14.A.1, reaction of “E2a” with

-   -   2-fluorobenzylamine,    -   benzyl alcohol,    -   (pyridin-4-yl)methanethiol,    -   aniline,    -   3-fluorophenylmethanethiol,    -   (pyridin-2-yl)methylamine,    -   4-fluorobenzyl alcohol,        gives the compounds

-   5-[5-(2-fluorobenzylamino)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-(5-benzyloxy-2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(pyridin-4-ylmethylsulfanyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-(5-phenylamino-2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(3-fluorophenylmethylsulfanyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    and simple oxidation thereof gives

-   5-[5-(3-fluorophenylmethylsulfinyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(pyridin-2-ylmethylamino)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(4-fluorobenzyloxy)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole.

14.B.2 Ether cleavage of the compounds obtained under 14.B.1 gives thefollowing dihydroxypyrazole derivatives

-   5-[5-(2-fluorobenzylamino)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,-   5-(5-benzyloxy-2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,-   5-[5-(pyridin-4-ylmethylsulfanyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,-   5-(5-phenylamino-2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,-   5-[5-(3-fluorophenylmethylsulfinyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,-   5-[5-(pyridin-2-ylmethylamino)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,-   5-[5-(4-fluorobenzyloxy)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole.

14.C

Analogous reaction of 5-[5-iodo-2,4-dimethoxyphenyl]1-phenyl-1H-pyrazolewith 4-fluorophenylmethanethiol gives the compound

-   5-[5-(4-fluorophenylmethylsulfanyl)-2,4-dimethoxyphenyl]1-phenyl-1H-pyrazole,    and oxidation thereof using perborate gives-   5-[5-(4-fluorophenylmethylsulfonyl)-2,4-dimethoxyphenyl]1-phenyl-1H-pyrazole.

Ether cleavage thereof gives5-[5-(4-fluorophenylmethylsulfonyl)-2,4-dihydroxyphenyl]-1-phenyl-1H-pyrazole.

Analogous reaction of5-[5-iodo-2,4-dimethoxyphenyl]1-(3-ethylphenyl)-1H-pyrazole and3-fluorothiophenol gives the compound

-   5-[5-(3-fluorophenylsulfonyl)-2,4-dihydroxyphenyl]1-(3-ethylphenyl)-1H-pyrazole.

14.D

Analogous reaction of5-[5-iodo-2,4-dimethoxyphenyl]1-(3-methylphenyl)-1H-pyrazole withthiophenol gives the compound

-   5-[5-phenylsulfanyl-2,4-dimethoxyphenyl]1-(3-methylphenyl)-1H-pyrazole,    and ether cleavage thereof gives-   5-[5-phenylsulfanyl-2,4-dihydroxyphenyl]1-(3-methylphenyl)-1H-pyrazole.

14.E

Analogous reaction of5-[5-iodo-2,4-dimethoxyphenyl]1-(4-nitrophenyl)-1H-pyrazole with2-fluorothiophenol gives the compound

-   5-[5-(2-fluorophenylsulfanyl)-2,4-dimethoxyphenyl]1-(4-nitrophenyl)-1H-pyrazole;    monoether cleavage thereof gives-   5-[5-(2-fluorophenylsulfanyl)-2-hydroxy-4-methoxyphenyl]1-(4-nitrophenyl)-1H-pyrazole;    and H₂ reduction thereof using Pd/C as catalyst gives the compound-   5-[5-(2-fluorophenylsulfanyl)-2-hydroxy-4-methoxyphenyl]1-(4-aminophenyl)-1H-pyrazole.

EXAMPLE 15

General reaction scheme for the preparation of compounds of the formulaI in which R² denotes an unsubstituted or substituted amide group

15.A

15.A.1 A mixture of 176.3 mg of “E2a”, 123.6 μl of diethylamine, 3 mg ofpalladium(II) acetate (47% of Pd), 179.1 μl of1,8-diazabicyclo[5.4.0]undec-7-ene, 2 ml of THF and 105.6 mg ofmolybdenum hexacarbonyl is irradiated in the microwave for 1 hour at120°. Conventional work-up gives5-[5-(N,N-diethylaminocarbonyl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole(“G1”).

15.A.2 Ether cleavage of “G1” using BBr₃ gives the compound5-[5-(N,N-diethylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole.

15.B. Analogous reaction of “E2a” and

-   -   aniline,    -   methylamine,    -   dimethylamine,    -   ethylamine,    -   N-propyl-N-methylamine,    -   N-cyclopentyl-N-methylamine,        gives the compounds

-   5-(5-phenylaminocarbonyl-2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N,N-dimethylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-ethylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,

-   5-[5-(N-propyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,    retention time [min] 1.325, M+H⁺[m/e] 386.85;

-   5-[5-(N-cyclopentyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole.

15.C Analogous reaction of5-[5-iodo-2,4-dimethoxyphenyl]1-(2-chloro-5-fluorophenyl)-1H-pyrazoleand C-benzo-1,3-dioxol-5-ylmethylamine gives the compound

-   5-{5-{N-[(benzo-1,3-dioxol-5-yl)methyl]aminocarbonyl}2,4-dihydroxyphenyl}-1-(2-chloro-5-fluorophenyl)-1H-pyrazole.

15.D Analogous reaction of5-[5-iodo-2,4-dimethoxyphenyl]1-(2-ethylphenyl)-1H-pyrazole andN-ethyl-N-methylamine gives the compound

-   5-[5-(N-ethyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-ethylphenyl)-1H-pyrazole.

15.E Analogous reaction of5-[5-iodo-2,4-dimethoxyphenyl]1-(2,3-dichlorophenyl)-1H-pyrazole andN-butyl-N-methylamine gives the compound

-   5-[5-(N-butyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2,3-dichlorophenyl)-1H-pyrazole.

15.F The preparation of the compound5-[5-(N-propyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-{4-[2-(4-methylpiperazin-1-yl)ethoxy]-phenyl}-1H-pyrazole(“GG”) is carried out analogously to the following reaction scheme

EXAMPLE 16

General reaction scheme for the preparation of compounds of the formulaI in which R² denotes an unsubstituted or substituted benzyl group

16.A

16.A.1 41 mg of PdCl₂(dppf) are added to 2.5 ml of benzyl zinc bromide(0.5M in THF), and the mixture is stirred for 5 minutes at roomtemperature under an argon atmosphere. A solution of 440.6 mg of “E2a”in 3 ml of THF is subsequently added dropwise, and the mixture isstirred at 45° for a further 30 minutes, then at 650 for 1 hour. Themixture is cooled, poured into saturated NH₄Cl solution and subjected toconventional work-up, giving a mixture of 3 compounds, which areseparated by chromatography (ISCO/120 g column; petroleum ether/ethylacetate: 95/5 to 60/40), giving 185 mg of “H1”, 188 mg of “H2” and 190mg of “H3”

16.A.2 Ether cleavage of “H1” using BBr₃ gives the compound5-(5-benzyl-2,4-dihydroxyphenyl)-1-(2-benzylphenyl)-1H-pyrazole,M+H⁺[m/e] 433.52.

16.A.3 Ether cleavage of “H3” using BBr₃ gives the compound5-(5-benzyl-2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,retention time [min] 1.741, M+H⁺[m/e] 377.84.

EXAMPLE 17

General reaction scheme for the preparation of compounds of the formulaI in which R² denotes an unsubstituted or substituted phenyl group

17.A

17.A.1 A mixture of 170.7 mg of benzeneboronic acid, 616.9 mg of “E2a”,10 ml of propanol, 1.79 mg of palladium(II) acetate, 3.1 mg oftriphenylphosphine, 2 ml of sodium carbonate solution and 1.2 ml ofwater is refluxed for 16 hours under an N₂ atmosphere. The mixture iscooled and subjected to conventional work-up, giving5-(5-phenyl-2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole (“K1”).

17.A.2 Ether cleavage of “K1” using BBr₃ gives the compound5-(5-phenyl-2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,retention time [min] 1.675, M+H⁺[m/e] 363.82.

The examples below relate to pharmaceutical compositions:

EXAMPLE A Injection Vials

A solution of 100 g of an active compound according to the invention andg of disodium hydrogenphosphate in 3 l of bidistilled water is adjustedto pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferredinto injection vials, lyophilised under sterile conditions and sealedunder sterile conditions. Each injection vial contains 5 mg of activecompound.

EXAMPLE B Suppositories

A mixture of 20 g of an active compound according to the invention with100 g of soya lecithin and 1400 g of cocoa butter is melted, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activecompound.

EXAMPLE C Solution

A solution is prepared from 1 g of an active compound according to theinvention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active compound according to the invention are mixed with99.5 g of Vaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active compound according to the invention, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active compound.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active compound according to the invention are introduced intohard gelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active compound.

EXAMPLE H Ampoules

A solution of 1 kg of an active compound according to the invention in60 l of bidistilled water is sterile filtered, transferred intoampoules, lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active compound.

1. Compounds of the formula I

in which R¹ denotes OH, OCH₃, OCF₃, OCHF₂, OBzl, OAc,p-methoxybenzyloxy, SH, S(O)_(m)CH₃, SO₂NH₂, Hal, CF₃ or CH₃, R², R³each, independently of one another, denote H, Hal, CN, NO₂, A, Alk,(CH₂)_(n)Ar, (CH₂)_(n)Het, (CH₂)_(n)COOH, (CH₂)_(n)COOA, COOAr, COOHet,CONH₂, CONHA, CONAA′, CONHAr, CONAAr, CON(Ar)₂, CONHHet, CON(Het)₂, NH₂,NHA, NHAr, NHHet, NAA′, NHCOA, NACOA′, NHCOAr, NHCOHet, NHCOOA, NHCOOAr,NHCOOHet, NHCONHA, NHCONHAr, NHCONHHet, OH, OA, OAr, OHet, SH,S(O)_(m)A, S(O)_(m)Ar, S(O)_(m)Het, SO₂NH₂, SO₂NHA, SO₂NAA′, SO₂NHAr,SO₂NAAr, SO₂NHHet, SO₂N(Ar)₂, SO₂N(Het)₂, CONH(CH₂)_(o)Het,NH(CH₂)_(o)Het, O(CH₂)_(o)Ar, S(O)_(m)(CH₂)_(o)Het, S(O)_(m)(CH₂)_(o)Ar,(CH₂)_(o)CH(Ar)CH₃, CONAR¹², SO₂NA(CH₂CONAA′), SO₂NH(CH₂Ar),SO₂NA[(CH₂)_(o)CN], SO₂NA(CH₂Ar), (CH₂)_(o)NHAr, (CH₂)_(o)NAAr,(CH₂)_(o)OAr, (CH₂)_(o)S(O)_(m)Ar, CH═CH—Ar, CHO, COA or R¹², R⁴, R⁵, R⁶each, independently of one another, denote H, Hal, CN, NO₂, A, Alk,(CH₂)_(n)Ar, (CH₂)_(n)Het, COOH, COOA, COOAr, COOHet, CONH₂, CONHA,CONAA′, CONHAr, CONAAr, CON(Ar)₂, CONHHet, CON(Het)₂, NH₂, NHA, NHAr,NHHet, NAA′, NHCOA, NACOA′, NHCOAr, NHCOHet, NHCOOA, NHCOOAr, NHCOOHet,NHCONHA, NHCONHAr, NHCONHHet, OH, OA, OAr, OHet, SH, S(O)_(m)A,S(O)_(m)Ar, S(O)_(m)Het, SO₂NH₂, SO₂NHA, SO₂NAA′, SO₂NHAr, SO₂NAAr,SO₂NHHet, SO₂N(Ar)₂, SO₂N(Het)₂, CONH(CH₂)_(o)Ar, NHCO(CH₂)_(o)Ar,NHCO(CH₂)_(o)OA or O(CH₂)_(o)Het, R⁴ and R⁵ together also denote OCH₂Oor OCH₂CH₂O, A, A′ each, independently of one another, denote unbranchedor branched alkyl having 1-10 C atoms, in which one, two or three CH₂groups may be replaced by O, S, SO, SO₂, NH, NR⁸ and/or by —CH═CH—groups and/or, in addition, 1-5H atoms may be replaced by F, Cl, Brand/or R⁷, Alk or cyclic alkyl having 3-7 C atoms, A and A′ togetheralso denote an alkylene chain having 2, 3, 4, 5 or 6 C atoms, which maybe substituted by CH₂OH, CH₂Br, CH₂NEt₂, and/or in which a CH₂ group maybe replaced by O, S, SO, SO₂, N, NH, NR⁸, NCOR⁸ or NCOOR⁸, Alk denotesalkenyl having 2-6 C atoms, R⁷ denotes COOR⁹, CONR⁹R¹⁰, NR⁹R¹⁰, NHCOR⁹,NHCOOR⁹ or OR⁹, R⁸ denotes cycloalkyl having 3-7 C atoms,cycloalkylalkylene having 4-10 C atoms, Alk or unbranched or branchedalkyl having 1-6 C atoms, in which one, two or three CH₂ groups may bereplaced by O, S, SO, SO₂, NH and/or, in addition, 1-5H atoms may bereplaced by F and/or Cl, R⁹, R¹⁰ each, independently of one another,denote H or alkyl having 1-5 C atoms, in which 1-3 CH₂ groups may bereplaced by O, S, SO, SO₂, NH, NMe or NEt and/or, in addition, 1-5Hatoms may be replaced by F and/or Cl, R⁹ and R¹⁰ together also denote analkylene chain having 2, 3, 4, 5 or 6 C atoms, in which a CH₂ group maybe replaced by O, S, SO, SO₂, NH, NR⁸, NCOR⁸ or NCOOR⁸, Ar denotesphenyl, naphthyl or biphenyl, each of which is un-substituted or mono-,di- or trisubstituted by Hal, A, OR¹¹, N(R¹¹)₂, NO₂, CN, phenyl,CON(R¹¹)₂, NR¹¹COA, NR¹¹CON(R¹¹)₂, NR¹¹SO₂A, COR¹¹, NR¹¹CO(CH₂)_(n)R¹¹,SO₂N(R¹¹)₂, S(O)_(m)A, —[C(R¹¹)₂]_(n)—COOR¹¹ and/or—O[C(R¹¹)₂]_(o)—COOR¹¹, Het denotes a mono- or bicyclic saturated,unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms,which may be mono-, di- or trisubstituted by Hal, A, OR¹¹, N(R¹¹)₂, NO₂,CN, COOR¹¹, CON(R¹¹)₂, NR¹¹COA, NR¹¹SO₂A, COR¹¹, SO₂NR¹¹, S(O)_(m)A, ═S,═NR¹¹ and/or ═O (carbonyl oxygen), R¹¹ denotes H or A, R¹² denotescycloalkyl having 3-7 C atoms or cycloalkylalkylene having 4-12 C atoms,Hal denotes F, Cl, Br or I, m denotes 0, 1 or 2, n denotes 0, 1, 2, 3 or4, o denotes 1, 2 or 3, and pharmaceutically usable derivatives, salts,solvates and stereoisomers thereof, including mixtures thereof in allratios.
 2. Compounds according to claim 1 in which R¹ denotes OH, OCH₃or SH, and pharmaceutically usable derivatives, salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 3.Compounds according to claim 1 in which R², R³ each, independently ofone another, denote H, Hal, A, (CH₂)_(n)Ar, (CH₂)_(n)Het, (CH₂)_(n)COOH,(CH₂)_(n)COOA, CONH₂, CONHA, CONAA′, CONHAr, CONHHet, NH₂, NHA, NHAr,NHHet, NAA′, S(O)_(m)A, S(O)_(m)Ar, SO₂NH₂, SO₂NHA, SO₂NAA′, SO₂NHAr,SO₂NAAr, SO₂NHHet, CONH(CH₂)_(o)Het, NH(CH₂)_(o)Het, O(CH₂)_(o)Ar,S(O)_(m)(CH₂)_(o)Het, S(O)_(m)(CH₂)_(o)Ar, (CH₂)_(o)CH(Ar)CH₃, CONAR¹²,SO₂NA(CH₂CONAA′), SO₂NH(CH₂Ar), SO₂NA[(CH₂)_(o)CN], SO₂NA(CH₂Ar),(CH₂)_(o)NHAr, (CH₂)_(o)NAAr, (CH₂)_(o)OAr, (CH₂)_(o)S(O)_(m)Ar or R¹²,and pharmaceutically usable derivatives, salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 4.Compounds according to claim 1 in which R⁴, R⁵, R⁶ each, independentlyof one another, denote H, Hal, CN, NO₂, A, (CH₂)_(n)Ar, COOH, COOA,CONH₂, CONHA, CONAA′, CONHAr, NH₂, NHA, NAA′, NHCOA, NHCOAr, NHCOHet,OH, OA, SO₂NH₂, SO₂NHA, SO₂NAA′, CONH(CH₂)_(o)Ar, NHCO(CH₂)_(o)Ar,NHCO(CH₂)_(n)OA or O(CH₂)_(o)Het, and pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 5. Compounds according to claim 1 inwhich A, A′ each, independently of one another, denote unbranched orbranched alkyl having 1-10 C atoms, in which one, two or three CH₂groups may be replaced by O, S, SO, SO₂, NH, NR⁸ and/or by —CH═CH—groups and/or, in addition, 1-5H atoms may be replaced by F, Cl, Brand/or R⁷, Alk or cyclic alkyl having 3-7 C atoms, A and A′ togetheralso denote an alkylene chain having 2, 3, 4, 5 or 6 C atoms, which maybe substituted by CH₂OH, CH₂Br or CH₂NEt₂, and/or in which a CH₂ groupmay be replaced by O, N, NH or NR⁸, and pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 6. Compounds according to claim 1 inwhich A, A′ each, independently of one another, denote unbranched orbranched alkyl having 1-6 C atoms, in which one, two or three CH₂ groupsmay be replaced by O, S, SO, SO₂, NH and/or by —CH═CH— groups and/or, inaddition, 1-5H atoms may be replaced by F, Cl and/or Br, Alk or cyclicalkyl having 3-7 C atoms, and pharmaceutically usable derivatives,salts, solvates and stereoisomers thereof, including mixtures thereof inall ratios.
 7. Compounds according to claim 1 in which R⁷ denotes COOR⁹,CONR⁹R¹⁰, NR⁹R¹⁰, NHCOR⁹, NHCOOR⁹ or OR⁹, and pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 8. Compounds according to claim 1 inwhich R⁸ denotes unbranched or branched alkyl having 1-6 C atoms, andpharmaceutically usable derivatives, salts, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 9. Compoundsaccording claim 1 in which R⁹, R¹⁰ each, independently of one another,denote H or alkyl having 1-5 C atoms, in which 1-5H atoms may bereplaced by F and/or Cl, and pharmaceutically usable derivatives, salts,solvates and stereoisomers thereof, including mixtures thereof in allratios.
 10. Compounds according to claim 1 in which A, A′ each,independently of one another, denotes unbranched or branched alkylhaving 1-6 C atoms, in which 1-5H atoms may be replaced by F, Cl and/orBr, or cyclic alkyl having 3-7 C atoms, and pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 11. Compounds according to claim 1 inwhich Ar denotes phenyl which is unsubstituted or mono-, di- ortrisubstituted by Hal, A, OR¹¹, N(R¹¹)₂, NR¹¹COA, NR¹¹CO(CH₂)OR¹¹,and/or —[C(R¹¹)₂]_(n)—COOR¹¹, and pharmaceutically usable derivatives,salts, solvates and stereoisomers thereof, including mixtures thereof inall ratios.
 12. Compounds according to claim 1 in which Het denotes amono- or bicyclic saturated or aromatic heterocycle having 1 to 2 Nand/or O atoms, which may be mono- or disubstituted by A, andpharmaceutically usable derivatives, salts, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 13. Compoundsaccording to claim 1 in which R¹ denotes OH, OCH₃ or SH, R², R³ each,independently of one another, denote H, Hal, A, (CH₂)_(n)Ar,(CH₂)_(n)Het, (CH₂)_(n)COOH, (CH₂)_(n)COOA, CONH₂, CONHA, CONAA′,CONHAr, CONHHet, NH₂, NHA, NHAr, NHHet, NAA′, S(O)_(m)A, S(O)_(m)Ar,SO₂NH₂, SO₂NHA, SO₂NAA′, SO₂NHAr, SO₂NAAr, SO₂NHHet, CONH(CH₂)_(o)Het,NH(CH₂)_(o)Het, O(CH₂)_(o)Ar, S(O)_(m)(CH₂)_(o)Het, S(O)_(m)(CH₂)_(o)Ar,(CH₂)_(o)CH(Ar)CH₃, CONAR¹², SO₂NA(CH₂CONAA′), SO₂NH(CH₂Ar),SO₂NA[(CH₂)_(o)CN], SO₂NA(CH₂Ar), (CH₂)_(o)NHAr, (CH₂)_(o)NAAr,(CH₂)_(o)OAr, (CH₂)_(o)S(O)_(m)Ar or R¹², R⁴, R⁵, R⁶ each, independentlyof one another, denote H, Hal, CN, NO₂, A, (CH₂)_(n)Ar, COOH, COOA,CONH₂, CONHA, CONAA′, CONHAr, NH₂, NHA, NAA′, NHCOA, NHCOAr, NHCOHet,OH, OA, SO₂NH₂, SO₂NHA, SO₂NAA′, CONH(CH₂)_(o)Ar, NHCO(CH₂)_(o)Ar,NHCO(CH₂)_(o)OA or O(CH₂)_(o)Het, R⁴ and R⁵ together also denote OCH₂Oor OCH₂CH₂O, A, A′ each, independently of one another, denote unbranchedor branched alkyl having 1-10 C atoms, in which one, two or three CH₂groups may be replaced by O, S, SO, SO₂, NH, NR⁸ and/or by —CH═CH—groups and/or, in addition, 1-5H atoms may be replaced by F, Cl, Brand/or R⁷, Alk or cyclic alkyl having 3-7 C atoms, A and A′ togetheralso denote an alkylene chain having 2, 3, 4, or 6 C atoms, which may besubstituted by CH₂OH, CH₂Br or CH₂NEt₂, and/or in which a CH₂ group maybe replaced by O, N, NH or NR⁸, R⁷ denotes COOR⁹, CONR⁹R¹⁰, NR⁹R¹⁰,NHCOR⁹, NHCOOR⁹ or OR⁹, R⁸ denotes unbranched or branched alkyl having1-6 C atoms, R⁹, R¹⁰ each, independently of one another, denote H oralkyl having 1-5 C atoms, in which 1-5H atoms may be replaced by Fand/or Cl, Ar denotes phenyl which is unsubstituted or mono-, di- ortrisubstituted by Hal, A, OR¹¹, N(R¹¹)₂, NR¹¹COA, NR¹¹CO(CH₂)_(o)R¹¹,and/or —[C(R¹¹)₂]_(n)—COOR¹¹, Het denotes a mono- or bicyclic saturatedor aromatic heterocycle having 1 to 2 N and/or O atoms, which may bemono- or disubstituted by A, R¹¹ denotes H or A, R¹² denotes cycloalkylhaving 3-7 C atoms or cycloalkylalkylene having 4-12 C atoms, Haldenotes F, Cl, Br or I, m denotes 0, 1 or 2, n denotes 0, 1, 2, 3 or 4,o denotes 1, 2 or 3, and pharmaceutically usable derivatives, salts,solvates and stereoisomers thereof, including mixtures thereof in allratios.
 14. Compounds according to claim 1 selected from the group5-(2-hydroxy-4-methoxyphenyl)-1-(3-nitrophenyl)-1H-pyrazole,5-(2-hydroxy-4-methyl-5-chlorophenyl)-1-phenyl-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(3,5-dichlorophenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(2-chloro-5-trifluoromethylphenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(2-ethylphenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(3-methoxyphenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(3-cyanophenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(3-trifluoromethylphenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(3-chlorophenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(3-fluorophenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-phenyl-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(4-trifluoromethylphenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(4-chlorophenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(4-aminosulfonylphenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(4-carboxyphenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(4-cyanophenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(3-chloro-4-methylphenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(4-methylphenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(4-bromophenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(2-methoxyphenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(2-fluorophenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(2-chlorophenyl)-1H-pyrazole,5-(2-hydroxy-4-fluorophenyl)-1-(2,6-difluorophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(3-nitrophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-nitrophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-aminophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(2-nitrophenyl)-1H-pyrazole5-(2-hydroxy-4-methoxyphenyl)-1-(2-aminophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-aminophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(2,4-difluorophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(3,5-dichlorophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(3-chloro-2-cyanophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(2,6-dichlorophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(2-chloro-5-trifluoromethylphenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(2-ethylphenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(3-methoxyphenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(3-cyanophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(3-trifluoromethylphenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(3-chlorophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(3-carboxyphenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(3-fluorophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-bromophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-phenyl-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-trifluoromethylphenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-chlorophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-aminosulfonylphenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-carboxyphenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-cyanophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(3-chloro-4-methylphenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-methylphenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(2,6-difluorophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-cyano-2-nitrophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(2-nitrophenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(4-ethoxycarbonylphenyl)-1H-pyrazole,5-(2-hydroxy-4-methoxyphenyl)-1-(2-aminophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(2,4-difluorophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(3,5-dichlorophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(3-chloro-2-cyanophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(2,6-dichlorophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(2-chloro-5-trifluoromethylphenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(2-ethylphenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(3-hydroxyphenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(3-cyanophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(3-trifluoromethylphenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(3-chlorophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(3-carboxyphenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(3-fluorophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-bromophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-phenyl-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-trifluoromethylphenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-chlorophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-aminosulfonylphenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-carboxyphenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-cyanophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-hydroxyphenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(3-chloro-4-methylphenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-methylphenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(2,6-difluorophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-cyano-2-nitrophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(2-nitrophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-ethoxycarbonylphenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(2-aminophenyl)-1H-pyrazole,5-(2,4-dimethoxyphenyl)-1-(4-nitrophenyl)-1H-pyrazole,5-(2,4-dimethoxyphenyl)-1-(4-aminophenyl)-1H-pyrazole,5-(2,4-dimethoxyphenyl)-1-(4-benzoylaminophenyl)-1H-pyrazole,5-(2,4-dimethoxyphenyl)-1-(4-acetylaminophenyl)-1H-pyrazole,5-(2,4-dimethoxyphenyl)-1-(4-propionylaminophenyl)-1H-pyrazole,5-(2,4-dimethoxyphenyl)-1-[4-(butyrylamino)phenyl]1H-pyrazole,5-(2,4-dimethoxyphenyl)-1-[4-(pyridin-4-ylcarbonylamino)phenyl]-1H-pyrazole,5-(2,4-dimethoxyphenyl)-1-[4-(phenylacetylamino)phenyl]1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-benzoylaminophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-acetylaminophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-(4-propionylaminophenyl)-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-[4-(butyrylamino)phenyl]1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-[4-(pyridin-4-ylcarbonylamino)phenyl]-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-[4-(phenylacetylamino)phenyl]1H-pyrazole,5-(2,4-dibenzyloxyphenyl)-1-(4-carboxyphenyl)-1H-pyrazole,5-(2,4-dibenzyloxyphenyl)-1-[4-(benzylaminocarbonyl)phenyl]-1H-pyrazole,5-(2,4-dibenzyloxyphenyl)-1-[4-(methylaminocarbonyl)phenyl]-1H-pyrazole,5-(2,4-dibenzyloxyphenyl)-1-[4-(ethylaminocarbonyl)phenyl]-1H-pyrazole,5-(2,4-dibenzyloxyphenyl)-1-[4-(propylaminocarbonyl)phenyl]-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-[4-(benzylaminocarbonyl)phenyl]1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-[4-(methylaminocarbonyl)phenyl]-1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-[4-(ethylaminocarbonyl)phenyl]1H-pyrazole,5-(2,4-dihydroxyphenyl)-1-[4-(propylaminocarbonyl)phenyl]1H-pyrazole,and pharmaceutically usable derivatives, salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 15.Compounds according to claim 1 selected from the group5-(5-aminosulfonyl-2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-ethyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N—N′-diethylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(piperidine-1-sulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-phenylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-phenylaminosulfonyl)-2-hydroxy-4-methoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-{5-[N-(2-fluorophenyl)aminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[N-(3-fluorophenyl)aminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[N-(4-fluorophenyl)aminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[N-(pyridin-3-yl)aminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(3-hydroxymethylpiperidine-1-sulfonyl)-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(3-bromomethylpiperidine-1-sulfonyl)-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-benzyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-benzyl-N′-methylaminosulfonyl)-2-methoxy-4-hydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N—N′-dimethylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-(2-bromoethyl)-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-cyclohexyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-(2,3-dibromopropyl)-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-butyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-{5-[N-(2-cyanoethyl)-N′-methylaminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-isopropyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[N-(dimethylaminocarbonylmethyl)-N′-methylaminosulfonyl]-2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(2-hydroxymethylpiperidine-1-sulfonyl)-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(morpholine-4-sulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazoleand5-{5-[N-(2-hydroxyethyl)-N′-(2-bromoethyl)aminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[N-(2-hydroxyethyl)-N′-(2-bromoethyl)aminosulfonyl]2-hydroxy-4-methoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole;5-{5-[2-(N,N′-diethylaminomethyl)piperidin-4-yl]sulfonyl}2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(1-methylpiperazin-4-yl)sulfonyl]2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-methylaminosulfonyl)-2,4-hydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-{5-[N-(pyridin-4-yl)aminosulfonyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-(N-phenylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,5-[5-(N-phenylaminosulfonyl)-2-hydroxy-4-methoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,5-[5-(N-benzylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,5-[5-(N-benzylaminosulfonyl)-2-hydroxy-4-methoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,5-[5-(N,N′-diethylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,5-[5-(N,N′-diethylaminosulfonyl)-2-hydroxy-4-methoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,5-[5-(ethylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,5-[5-(ethylaminosulfonyl)-2-hydroxy-4-methoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,5-[5-(aminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,5-[5-(aminosulfonyl)-2-hydroxy-4-methoxyphenyl]1-(2-methylphenyl)-1H-pyrazole,5-[5-iodo-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-iodo-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-carboxyethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-methoxycarbonylethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-(2-phenylethyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(2-phenylethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-(2-phenyl-2-methoxyethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-styryl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-{5-[2-(pyridin-4-yl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[2-(pyridin-4-yl)vinyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[2-(pyridin-2-yl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[2-(4-fluorophenyl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[2-(3-fluorophenyl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[2-(2-fluorophenyl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[1-(4-fluorophenyl)ethyl]2,4-dihydroxyphenyl}-1-phenyl-1H-pyrazole,5-{5-[2-(3-(aminomethylcarbonylamino)phenyl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole

5-{5-[2-(3-carboxyphenyl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[2-(2-chlorophenyl)ethyl]2,4-dihydroxyphenyl}-1-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1H-pyrazole,5-{5-propyl-2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole5-{5-cyclopropylmethyl-2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-(2-methylbutyl)-2,4-dihydroxyphenyl}-1-(3-methylphenyl)-1H-pyrazole,5-{5-(2-fluoropropyl)-2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[2-(4-methylphenyl)ethyl]2,4-dihydroxyphenyl}-1-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1H-pyrazole,5-{5-(2-phenylpropyl)-2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-{5-(2-phenylpropyl)-2,4-dihydroxyphenyl}-1-(2-aminophenyl)-1H-pyrazole,5-[5-phenylaminomethyl-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-phenylaminomethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-phenoxymethyl-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-phenoxymethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-phenylthiomethyl-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-phenylthiomethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-(4-methoxyphenylthiomethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-phenylsulfinylmethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-(4-methoxyphenylsulfinylmethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-phenylsulfonylmethyl-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-(4-methoxyphenylsulfonylmethyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-phenylsulfanyl-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-phenylsulfanyl-2-hydroxy-4-methoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-phenylsulfonyl-2-hydroxy-4-methoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-phenylsulfonyl-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(2-fluorobenzylamino)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-(5-benzyloxy-2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(pyridin-4-ylmethylsulfanyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-(5-phenylamino-2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(3-fluorophenylmethylsulfinyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(pyridin-2-ylmethylamino)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(4-fluorobenzyloxy)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(4-fluorophenylmethylsulfonyl)-2,4-dihydroxyphenyl]1-phenyl-1H-pyrazole,5-[5-(3-fluorophenylsulfonyl)-2,4-dihydroxyphenyl]1-(3-ethylphenyl)-1H-pyrazole,5-[5-phenylsulfanyl-2,4-dihydroxyphenyl]1-(3-methylphenyl)-1H-pyrazole,5-[5-(2-fluorophenylsulfanyl)-2-hydroxy-4-methoxyphenyl]1-(4-nitrophenyl)-1H-pyrazole,5-[5-(2-fluorophenylsulfanyl)-2-hydroxy-4-methoxyphenyl]1-(4-aminophenyl)-1H-pyrazole,5-[5-(N,N-diethylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-(5-phenylaminocarbonyl-2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N,N-dimethylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-ethylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-propyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-cyclopentyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,5-{5-{N-[(benzo-1,3-dioxol-5-yl)methyl]aminocarbonyl}2,4-dihydroxyphenyl}-1-(2-chloro-5-fluorophenyl)-1H-pyrazole,5-[5-(N-ethyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-ethylphenyl)-1H-pyrazole,5-[5-(N-butyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2,3-dichlorophenyl)-1H-pyrazole,5-[5-(N-propyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-{4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-1H-pyrazole,5-(5-benzyl-2,4-dihydroxyphenyl)-1-(2-benzylphenyl)-1H-pyrazole,5-(5-benzyl-2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole,5-(5-phenyl-2,4-dihydroxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole, andpharmaceutically usable derivatives, salts, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 16. Compoundsaccording to claim 1 selected from the group5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-methylphenyl)-1H-pyrazole,5-[5-(N-propyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]1-(2-fluorophenyl)-1H-pyrazole,5-[5-(N-isopropyl-N′-methylaminosulfonyl)-2,4-dihydroxyphenyl]-1-(2-chlorophenyl)-1H-pyrazole,5-{5-[2-(2-fluorophenyl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole,5-[5-(N-propyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-(2-chlorophenyl)-1H-pyrazole,5-(2,4-dihydroxy-5-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazole,5-(2,4-dihydroxy-5-chlorophenyl)-1-(2-fluorophenyl)-1H-pyrazole,5-(2,4-dihydroxy-5-bromophenyl)-1-(2-ethylphenyl)-1H-pyrazole,5-[5-(N-propyl-N-methylaminocarbonyl)-2,4-dihydroxyphenyl]1-{4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-1H-pyrazole,and pharmaceutically usable derivatives, salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 17.Process for the preparation of compounds of the formula I according toclaim 1 and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, characterised in that a) a compound of theformula II

in which R¹, R² and R³ have the meanings indicated in claim 1, and Xdenotes H or methyl, is reacted with a compound of the formula III

in which R⁴, R⁵ and R⁶ have the meanings indicated in claim 1, theresultant compound in which X denotes methyl is subsequently, ifdesired, converted into a compound of the formula I in which X denotes Hby ether cleavage, and/or in that one or more radical(s) R¹, R², R³, R⁴and/or R⁵ in a compound of the formula I are converted into one or moreradical(s) R¹, R², R³, R⁴ and/or R⁵ by, for example, i) reducing a nitrogroup to an amino group, ii) hydrolysing an ester group to a carboxylgroup, iii) converting an amino group into an alkylated amine byreductive amination, iv) converting a carboxyl group into asulfonamidocarbonyl group, v) converting an acid chloride into an amide,and/or a base or acid of the formula I is converted into one of itssalts.
 18. Medicaments comprising at least one compound according toclaim 1 and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, andoptionally excipients and/or adjuvants.
 19. Use of compounds accordingto claim 1, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, for thepreparation of a medicament for the treatment and/or prophylaxis ofdiseases in which the inhibition, regulation and/or modulation of HSP90plays a role.
 20. Use for the preparation of a medicament for thetreatment and/or prophylaxis of diseases in which the inhibition,regulation and/or modulation of HSP90 plays a role of compounds of claim1, and pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios, for the preparationof a medicament for the treatment or prevention of tumour diseases,viral diseases, for immune suppression in transplants,inflammation-induced diseases, cystic fibrosis, diseases associated withangiogenesis, infectious diseases, autoimmune diseases, ischaemia,fibrogenetic diseases, for the promotion of nerve regeneration, forinhibiting the growth of cancer, tumour cells and tumour metastases, forthe protection of normal cells against toxicity caused by chemotherapy,for the treatment of diseases in which incorrect protein folding oraggregation is a principal causal factor.
 21. Use according to claim 20,where the tumour diseases are fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumour, leiosarcoma, rhabdomyosarcoma,colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer,prostate cancer, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, syringocarcinoma, sebaceous cell carcinoma, papillarycarcinoma, papillary adenocarcinomas, cystadenocarcinomas, bone marrowcarcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bileduct carcinoma, choriocarcinoma, seminoma, embryonic carcinoma, Wilm'stumour, cervical cancer, testicular tumour, lung carcinoma, small-celllung carcinoma, bladder carcinoma, epithelial carcinoma, glioma,astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma,haemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,melanoma, neuroblastoma, retinoblastoma, leukaemia, lymphoma, multiplemyeloma, Waldenström's macroglobulinaemia and heavy-chain disease. 22.Use according to claim 20, where the viral pathogen of the viraldiseases is selected from the group consisting of hepatitis type A,hepatitis type B, hepatitis type C, influenza, varicella, adenovirus,herpes simplex type I (HSV-I), herpes simplex type II (HSV-II), cattleplague, rhinovirus, echovirus, rotavirus, respiratory syncytial virus(RSV), papillomavirus, papovavirus, cytomegalovirus, echinovirus,arbovirus, huntavirus, Coxsackie virus, mumps virus, measles virus,rubella virus, polio virus, human immunodeficiency virus type I (HIV-I)and human immunodeficiency virus type II (HIV-II).
 23. Use according toclaim 20, where the inflammation-induced diseases are rheumatoidarthritis, asthma, multiple sclerosis, type 1 diabetes, lupuserythematosus, psoriasis and inflammatory bowel disease.
 24. Useaccording to claim 20, where the diseases in connection withangiogenesis are diabetic retinopathy, haemangiomas, endometriosis andtumour angiogenesis.
 25. Use according to claim 20, where thefibrogenetic diseases are dermatosclerosis, polymyositis, systemiclupus, cirrhosis of the liver, keloid formation, interstitial nephritisand pulmonary fibrosis.
 26. Use according to claim 20, where thediseases in which incorrect protein folding or aggregation is aprincipal causal factor are scrapie, Creutzfeldt-Jakob disease,Huntington's or Alzheimer's.
 27. Medicaments comprising at least onecompound according to claim 1 and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and at least one further medicament activecompound.
 28. Set (kit) consisting of separate packs of (a) an effectiveamount of a compound according to claim 1 and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and (b) an effective amount of a furthermedicament active compound.
 29. Intermediate compounds of the formulaI-I

in which R¹ denotes OCH₃, OBzl, OAc, p-methoxybenzyloxy or 1, R², R³denote H R⁴, R⁵, R⁶ each, independently of one another, denote H, Hal,CN, NO₂, A, COOH, COOA, NH₂, OH, OA or SO₂NH₂, X denotes CH₃, Bzl, Ac orp-methoxybenzyl, A denotes unbranched or branched alkyl having 1-6 Catoms, in which 1-5H atoms may be replaced by F and/or Cl, or cyclicalkyl having 3-7 C atoms, and salts thereof.